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| United States Patent |
5,527,948
|
|
Okita
, et al.
|
June 18, 1996
|
Naphthalene derivative
Abstract
Naphthalene derivatives of the formula:
##STR1##
wherein R.sup.1, represents a hydrogen atom, a lower alkyl group or an
acyl group; R.sup.2 independently represents a hydrogen atom, a lower
alkyl group, a lower alkoxy group, a halogen atom, a cycloalkyl group, a
cycloalkylalkyl group, a hydroxyl group, an aryl group which may be
substituted, an arylalkyl group whose aryl group may be substituted, a
heteroaryl group, or a heteroaryllakyl group; R.sup.3 represents a
hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl group
which may have a substituent, an arylalkyl group whose aryl group may be
substituted, an arylalkenyl group whose aryl group may be substituted, a
cycloalkyl group, an alkoxyalkyl group, a heteroaryl group, a
heteroarylalkyl group, a carboxyl group, a carboxyalkyl group, an
aminoalkyl group, or a cyano group; R.sup.6 is C.sub.1-6 alkyl; and m is 0
or an integer of from 1 to 2 useful in treating autoimmune diseases are
disclosed.
| Inventors:
|
Okita; Makoto (Tsuchiura, JP);
Shirota; Hiroshi (Tsukuba, JP);
Tanaka; Masayuki (Ushiku, JP);
Kaneko; Toshihiko (Ushiku, JP);
Tagami; Katsuya (Ibaraki, JP);
Hibi; Shigeki (Tsukuba, JP);
Okamoto; Yasushi (Tsukuba, JP);
Nomoto; Seiichiro (Ushiku, JP);
Suzuki; Takeshi (Ushiku, JP);
Chiba; Kenichi (Tsuchiura, JP);
Goto; Masaki (Tsukuba, JP);
Hashida; Ryoichi (Tsukuba, JP);
Ono; Hideki (Tsukuba, JP);
Ohhara; Hideto (Tsukuba, JP);
Sakurai; Hideki (Tsukuba, JP);
Souda; Shigeru (Ushiku, JP);
Machida; Yoshimasa (Tsukuba, JP);
Katayama; Kouichi (Tsukuba, JP);
Yamatsu; Isao (Ushiku, JP)
|
| Assignee:
|
Eisai Corp. Ltd. (JP)
|
| Appl. No.:
|
402569 |
| Filed:
|
March 13, 1995 |
Foreign Application Priority Data
| Dec 28, 1988[JP] | 63-331621 |
| Current U.S. Class: |
560/56; 560/53; 568/328 |
| Intern'l Class: |
C07C 069/76; C07C 049/115 |
References Cited
Other References
CA 106:40316 1986.
|
Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Nixon & Vanderhye
Parent Case Text
This is a continuation of application Ser. No. 08/176,894, filed Jan. 3,
1994, now abandoned which is a division of Ser. No. 07/774,237, filed Oct.
10, 1991 now U.S. Pat. No. 5,298,649 which is a division of Ser. No.
07/451,468, filed Dec. 15, 1989 now U.S. Pat. No. 5,134,111.
Claims
We claim:
1. A compound of the formula:
##STR160##
wherein R.sup.1, represents a hydrogen atom, a lower alkyl group or an
acyl group;
R.sup.2 independently represents a hydrogen atom, a lower alkyl group, a
lower alkoxy group, a halogen atom, a cycloalkyl group, a cycloalkylalkyl
group, a hydroxyl group, an aryl group which may be substituted, an
arylalkyl group whose aryl group may be substituted, a heteroaryl group,
or a heteroaryllakyl group;
R.sup.3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl
group, an aryl group which may have a substituent, an arylalkyl group
whose aryl group may be substituted, an arylalkenyl group whose aryl group
may be substituted, a cycloalkyl group, an alkoxyalkyl group, a heteroaryl
group, a heteroarylalkyl group, a carboxyl group, a carboxyalkyl group, an
aminoalkyl group, or a cyano group;
R.sup.6 is C.sub.1-6 alkyl; and
m is 0 or an integer of from 1 to 2.
Description
INDUSTRIAL FIELD OF UTILIZATION
This invention relates to naphthalene derivatives. More particularly, it
relates to naphthalene derivatives which have a good efficacy as
medicines.
BACKGROUND OF THE INVENTION AND PRIOR ART
Interleukin-1 (hereinafter referred to simply as IL-1) is a protein
produced from macrophages, neutrocytes and the like and is a central
factor of inflammation and immune systems. Its relation with autoimmune
diseases and inflammatory diseases. typical of which is chronic articular
rheumatism, is being clarified.
Especially, according to the recent report, it has been found that IL-1 is
detected in rheumatoid chronica, particularly in the synovial fluid of
chronic articular rhumatics, and the lymph cell emigration factor consists
chiefly in IL-1 and that the peripheral hemomonocyte of rhumatics in
activity is promoted in the IL-1 productivity.
We attempted to mainly suppress the production of IL-1 so that the
autoimmune diseases, such as chronic articular rheumatism, and diseases
such as inflammatory diseases were cured and prevented.
The chronic articular rheumatism is a chronic inflammatory disease whose
cause is unknown. For medicinal therapy, non-steroid, antiphlogistic drugs
have been used and their utility is not satisfactory in respect of the
curing and side effects.
We have made extensive studies on compounds having the IL-1 production
inhibiting action over a long period of time and found that naphthalene
derivatives are excellent in the action.
Naphthalene derivatives are disclosed, for example, in Japanese Laid-open
Patent Application No. 61-263943, as having the 5-lippoxigenase inhibiting
action.
EMBODIMENTS AND FEATURES OF THE INVENTION
Under these circumstances in the art, studies and investigation have been
made on compounds having good IL-1 production inhibiting action, with the
result that it has been found that naphthalene derivatives of the
following chemical structural formula can achieve this purpose.
The compounds of the invention are naphthalene derivatives of the following
general formula (I), and pharmaceutically acceptable salts thereof,
##STR2##
[wherein R.sup.1 represents a hydrogen atom, a lower alkyl group or an
acyl group;
R.sup.2 independently represents a hydrogen atom, a lower alkyl group, a
lower alkoxy group, a halogen atom, a cycloalkyl group, a cycloalkylalkyl
group, a hydroxyl group, an aryl group which may be substituted, an
arylalkyl group whose aryl group may be substituted, a heteroaryl group,
or a heteroarylalkyl group;
R.sup.3 and R.sup.4 are the same or different and represent a hydrogen
atom, a lower alkyl group, a lower alkenyl group, an aryl group which may
have a substituent, an arylalkyl group whose aryl group may be
substituted, an arylalkenyl group whose aryl group may be substituted, a
cycloalkyl group, an alkoxyalkyl group, a heteroaryl group, a
heteroarylalkyl group, a carboxyl group, a carboxyalkyl group, an
aminoalkyl group, or a cyano group;
R.sup.5 represents a group of the formula, --OR.sup.7, (wherein R.sup.7
represents a hydrogen atom or a lower alkyl group), or a group of the
formula,
##STR3##
(wherein R.sup.8 and R.sup.9 are the same or different and represent a
hydrogen atom or a lower alkyl group, or R.sup.8 and R.sup.9 can form,
along with the nitrogen atom bonded with R.sup.8 and R.sup.9, a ring which
may contain an oxygen atom);
R.sup.6 independently represents a hydrogen atom, a halogen atom, a lower
alkyl group, a lower alkoxy group, a hydroxyl group, an amino group, an
arylalkyl group, or an aryl group; and
m is 0 or an integer of from 1 to 2, and n is 0 or an integer of from 1 to
4.]
In the present specification, the position number of the respective carbon
atoms in the naphthalene ring is determined in the following manner:
##STR4##
In the definitions of the compound (I) of the invention, the lower alkyl
group represented by R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 is a linear or branched alkyl group having 1 to 6
carbon atoms and includes, for example, a methyl group, an ethyl group, a
propyl group, an isopropyl group, a butyl group, an isobutyl group, a
sec-butyl group, a tert-butyl group, a pentyl group (amyl group), an
isopentyl group, a neopentyl group, a tert-pentyl group, a 1-methylbutyl
group, a 2-methylbutyl group, a 1,2-dimethylpropyl group, a hexyl group,
an isohexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a
3-methylpentyl group, a 1,1-dimethylbutyl group, a 1,3dimethylbutyl, a
2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl
group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl
group, a 1,1,2-trimethylpropyl group, a, 1,2,2-trimethylpropyl group, a
1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl group or the like.
Of these, a methyl group, an ethyl group, a propyl group and an isopropyl
group are preferred. Most preferably, a methyl group is used.
The lower alkenyl group defined by R.sup.3 and R.sup.4 is an alkenyl group
derived from the above-defined lower alkyl group having from 1 to 6 carbon
atoms.
The lower alkoxy group defined by R.sup.2 is a lower alkoxy group derived
from the above-defined lower alkyl group having from 1 to 6 carbon atoms.
Preferable examples include a methoxy group, an ethoxy group, an n-propoxy
group, an isopropoxy group, an n-butoxy group and the like.
The halogen atom defined by R.sup.2 is chlorine, bromine, iodine or
fluorine.
The cycloalkyl group defined by R.sup.2 is a cycloalkyl group having from 3
to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or the like.
The cycloalkylalkyl group is a group derived from the above cycloalkyl
group and typical examples include cyclopentylmethyl, cyclopropylmethyl,
cyclohexylmethyl, cyclohexylethyl and the like groups.
The aryl group defined by R.sup.2 and R.sup.6 is, for example, a phenyl
group, a naphthyl group or the like, which may be substituted with a lower
alkyl group such as a methyl group, an ethyl group or the like, a halogen
atom, a lower alkoxy group, or the like. The arylalkyl group whose aryl
group may be substituted is an arylalkyl group derived from the above aryl
group. Most preferably, a benzyl group, a phenetyl group or the like.
The heteroaryl group defined by R.sup.2, R.sup.3 and R.sup.4 is a group
derived from a heterocyclic ring such as a pyridyl group, a furyl group, a
pyrimidyl group or the like. The heteroarylalkyl group is, for example, a
pyridylmethyl group.
In the definition of the term "aryl group which may be substituted" used in
R.sup.2, R.sup.3 and R.sup.4, the substituent is, for example, a lower
alkyl group such as a methyl group, an ethyl group, a propyl group or the
like, a lower alkoxy group such as a methoxy group, an ethoxy group or the
like, or a halogen atom. The term "an arylalkyl group whose aryl group may
be substituted" is intended to mean a group derived from the aryl group
which may be substituted.
The acyl group defined by R.sup.1 represents residues of organic acids such
as aliphatic saturated carboxylic acids, aliphatic unsaturated carboxylic
acids, carbocyclic carboxylic acids or heterocyclic carboxylic acids.
Specific examples include lower alkanoyl group such as formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the
like, aroyl groups such as benzoyl, toloyl, naphthoyl and the like, and
heteroaroyl group such as furoyl, nicotinoyl, isonicotinoyl and the like.
The term "to form, along with the nitrogen atom bonded with R.sup.8 and
R.sup.9, a ring which may contain an oxygen atom" used in the definition
of R.sup.3 and R.sup.4 is intended to mean, for example, the following
groups
##STR5##
The compounds of the invention are characterized in that they have such a
structure that the naphthalene ring is substituted with --OR.sup.1 at the
4 position (wherein R.sup.1 has the same meaning as defined before) and
also with a group of the formula,
##STR6##
wherein R.sup.3, R.sup.4 and R.sup.5 have, respectively, meanings as
defined before).
In the above formula, R.sup.1 is most preferably a hydrogen atom or an acyl
group.
Most preferably, R.sup.3 and R.sup.4 are independently a hydrogen, atom, a
lower alkyl group, an aryl group or an arylalkyl group.
In the general formula (I), the groups represented by the formula,
--(R.sup.2).sub.m, independently a hydrogen atom, a lower alkyl group, a
lower alkoxy group, a halogen atom, a cycloalkyl group, a cycloalkylalkyl
group, a hydroxyl group, an aryl group which may be substituted, an
arylalkyl group whose aryl group may be substituted, a heteroaryl group or
a heteroarylalkyl group. The term "independently" is intended to mean that
when m is equal to 2, the substituents at the 2 and 3 positions of the
naphthalene ring may be the same or different. More specifically, the
formula (I) may be represented by the following formula (I')
##STR7##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and n have,
respectively, the same meanings as defined before, and R.sup.a and R.sup.b
may be the same or different and represent a hydrogen atom, a lower alkyl
group, a lower alkoxy group, a halogen atom, a cycloalkyl group, a
cycloalkylalkyl group, a hydroxyl group, an aryl group which may be
substituted, an arylalkyl group whose aryl group may be substituted, a
heteroaryl group or a heteroarylalkyl group).
Preferably, m=1 and R.sup.2 is at the 3 position of the naphthalene ring.
In the general formula (I), the groups represented by the formula,
--(R.sup.6).sub.n, Independently a hydrogen atom, a halogen atom, a lower
alkyl group, a lower alkoxy group, a hydroxyl group, an amino group, an
aryl group or an arylalkyl group. The term "independently" means that when
n is equal to 2, 3 or 4, the substituents at the 5 to 8 positions of the
naphthalene group may be the same or different. More specifically, the
general formula (I) may be represented by the following formula (I'')
##STR8##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and m have,
respectively, the same meanings as defined before, and R.sup.o, R.sup.d,
R.sup.e and R.sup.f may be the same or different and represent a hydrogen
atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a
hydroxyl group, an amino group, an aryl group or an arylalkyl group).
In the practice of the invention, the most preferable compound group
includes the naphthalene derivatives of the following general formula (A)
or their pharmaceutically acceptable salts
##STR9##
[wherein R.sup.1 represents a hydrogen atom, a lower alkyl group or an
acyl group;
R.sup.x represents a hydrogen atom, a lower alkyl group, a lower alkoxy
group, a halogen atom, a cycloalkyl group, a cycloalkylalkyl group, a
hydroxyl group, an aryl group which may be substituted, an arylalkyl group
whose aryl group may be substituted, a heteroaryl group, or a
heteroarylalkyl group;
R.sup.3 and R.sup.4 may be the same of different and represent a hydrogen
atom, a lower alkyl group, a lower alkenyl group, an aryl group which may
be substituted, an arylalkyl group whose aryl group may be substituted, an
arylalkenyl group whose aryl group may be substituted, a cycloalkyl group,
an alkoxyalkyl group, a heteroaryl group, a heteroarylalkyl group, a
carboxyl group, a carboxyalkyl group, an aminoalkyl group or a cyano
group;
R.sup.5 represents a group of the formula, --OR.sup.7, (wherein R.sup.7
represents a hydrogen atom or a lower alkyl group), or a group of the
formula,
##STR10##
(wherein R.sup.5 and R.sup.9 are the same or different and represent a
hydrogen atom or a lower alkyl group, or R.sup.8 and R.sup.9 can form,
along with the nitrogen atom bonded with R.sup.8 and R.sup.9, a ring which
may contain an oxygen atom); and
R.sup.9 represents a hydrogen atom, a halogen atom, a lower alkyl group, a
lower alkoxy group, a hydroxyl group, an amino group, an arylalkyl group
or an aryl group.]
This is the case where, in the general formula (I) of the compounds of the
invention, m and n are, respectively, equal to 1, R.sup.2 is at the 3
position of the naphthalene ring [R.sup.x in the formula (A)], and R.sup.6
is at the 5 position of the naphthalene ring [R.sup.9 in the formula (A)].
In the formula (A), R.sup.1 is most preferably a hydrogen atom and the
second most preferably an acyl group.
R.sup.x is preferably a hydrogen atom, a lower alkyl group, a lower alkoxy
group or a halogen atom, of which a lower alkoxy group is more preferred
and a methoxy group is most preferred.
As preferred among the above-defined substituents, R.sup.3 and R.sup.4 are
the same or different and represent a hydrogen atom or a lower alkyl
group. Among lower alkyl groups, a methyl group and an ethyl group are
most preferred.
R.sup.5 is preferably a group of the formula, --OR.sup.7, wherein R.sup.7
is most preferably a hydrogen atom or a lower alkyl group.
R.sup.9 is preferably a hydrogen atom, a lower alkyl, group, a lower alkoxy
group, a halogen atom, an aryl group or an arylalkyl group, of which the
lower alkyl group such as a methyl group, an ethyl group or the like is
most preferred.
The pharmaceutically acceptable salts used in the invention are ordinary
innoxious salts such as, for example, inorganic acid salts such as
hydrochlorides, hydrobromides, sulfates, phosphates and the like, organic
acid salts such as acetates, maleates, tartrates, methanesulfonates,
benzenesulfonates, toluenesulfonates and the like, and salts with amino
acids such as alginine, aspartic acid, glutamic acid and the like.
The compounds of the invention have asymmetric carbon in the molecule and
may include various steric isomers. In the practice of the invention,
individual isomers and mixtures thereof are, of course, within the scope
of the invention.
If hydrates are formed depending on the type of compound, such hydrates are
also within the scope of the invention.
The compounds of the invention may be prepared by various processes,
typical of which are the following processes.
##STR11##
(in the above series of the formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, m and n have, respectively, the same meanings as defined
before).
More particularly, the phosphoric acid ester of the general formula (III),
(IV) or (V) is caused to the Wittig reaction with the aldehyde or ketone
compound of the general formula (II), thereby obtaining intended substance
(I).
In the general formula (IV), R.sup.h and R.sup.i, respectively, represent a
lower alkyl group and most preferably an ethyl group.
Favorable results are obtained when these reactions are carried out in the
presence of bases.
Examples of the base include sodium hydride, potassium hydride, sodium
amide, sodium methoxide, sodium ethoxide, t-BuOK, MeLi, n-BuLi, and the
like.
The reaction may be effected in solvent-free condition or in solvent.
Examples of such a solvent include alcohols such as methanol, ethanol and
the like, benzene, tetrahydrofuran, dimethoxyethane, dimethylformamide
(DMF), dimethylsulfoxide and the like. The reaction temperature is from
-40.degree. C. to the boiling point of solvent, preferably from about
0.degree. to 70.degree. C.
In the intended substances represented by the general formula (I), there
exist trans-form products and cis-form products depending on the type of
substituent. According to the above process, the product is made
predominantly of the trans isomer. If it is desired to convert the
trans-form product to the cis-form product, the conversion easily
proceeds, for example, by subjecting the trans-form product to irradiation
with light from a high pressure mercury lamp using a Pyrex filter.
As the sensitizers for the reaction, there can be mentioned acetone,
propiophenone, acetophenone, benzophenone, triphenylene,
2-acetonaphthalene, 1-naphthyl phenyl ketone, 1-acetonaphthone and the
like.
The solvents for the reaction include alcohols such as methanol, ethanol
and the like, ketones such as acetone, methyl ethyl ketone, benzophenone
and the like, benzene, acetonitrile, and the like.
The reaction temperature is from -78.degree. C. to 40.degree. C.,
preferably from about 0.degree. to 30.degree. C.
The intended substances wherein R.sup.5 is a hydroxyl group can be prepared
according to the following procedure.
The substances of the general formula (I) are the case where R.sup.5 is of
the formula, --OR.sup.7, (wherein R.sup.7 has the same meaning as defined
before), and when R.sup.7 is a lower alkyl group, they are in the form of
esters. The hydrolysis of the ester (VI) by a usual manner results in
carboxylic acid (VII) which is one of the intended substances
##STR12##
(in the series of the formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.7, m and n have, respectively, the same meanings as defined before).
If a trans or cis-form product is desired for the intended substance of the
above formula (VII), such a product can easily be obtained by the use of a
trans or cis-form compound as the starting compound (VI).
The hydrolysis reaction is carried out by a usual manner in a solvent such
as water or a solvent miscible with water and selected, for example, from
methanol, ethanol, tetrahydrofuran, acetonitrile, acetone and the like, in
the presence of bases.
The bases include alkali metal carbonates such as sodium carbonate,
potassium carbonate and the like, and alkali hydroxides such as sodium
hydroxide, potassium hydroxide and the like.
The reaction temperature is about 0.degree. C. or in the range of from room
temperature to the boiling point of the solvent used.
The intended substance where R.sup.1 is a hydrogen can be prepared
according to the following procedure.
The substances of the formula (I) wherein R.sup.1 is an acryl group are
esters. When the ester (VIII) is hydrolyzed by a usual manner, a naphthol
derivative (IX) which is one of the intended substances can be obtained.
##STR13##
(wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, m and n have,
respectively the same meanings as defined before, and R.sup.1' represents
an acyl group).
In the substances represented by the above formula (IX), if a trans or
cis-form product is desired, such a product can easily be obtained by the
use of a trans or cis-form compound as the starting compound (VIII).
The reaction is carried out by a usual manner in a solvent such as water or
a solvent miscible with water and selected, for example, from methanol,
ethanol, tetrahydrofuran, acetonitrile, acetone and the like, in the
presence of bases.
Examples of the base include alkali metal carbonates such as sodium
carbonate, potassium carbonate and the like, and alkali hydroxides such as
sodium hydroxide, potassium hydroxide and the like.
The reaction temperature is about 0.degree. C. or in the range of from room
temperature to the boiling point of the solvent used.
Naphthol derivatives of the general formula (I) wherein R.sup.5 is a
hydroxyl group and R.sup.1 is a hydrogen atom may be obtained by
hydrolyzing the starting substance (VI) wherein R.sup.1 is a hydrogen
atom, or by hydrolyzing the starting substance (VIII) wherein R.sup.5 is a
hydroxyl group.
The compound wherein R.sup.1 is a hydrogen atom or which has a hydroxyl
group at the 4 position of the naphthalene ring can be prepared according
to the following procedure.
##STR14##
(wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, m and n have,
respectively the same meanings as defined before, and Y represents a
protective group for the hydroxyl group).
More particularly, the compound of the general formula (X) wherein the
hydroxyl group is appropriately protected with a protective group is used
as a starting material and is hydrolyzed by a usual manner to obtain
compound (IX) which is one of the intended substances. The protective
group includes, for example, not only a benzyl group, a p-methoxybenzyl
group, a furan-2-yl group and a pyran-2-yl group, but also acetal
protective groups such as a methoxymethyl group, an ethoxymethyl group, a
methoxyethoxymethyl group and the like. Most preferably, a methoxymethyl
group is used.
The solvents for the reaction include water, or solvents miscible, with
water and including, for example, ethers such as tetrahydrofuran, dioxane
and the like, alcohols such as methanol, ethanol and the like, and
acetone, acetonitrile and the like. In addition, esters such as ethyl
acetate, and aromatic hydrocarbon groups such as benzene, toluene and the
like are also usable.
The acids are, for example, hydrochloric acid, sulfuric acid,
p-toluenesulfonic acid, D-10-camphorsulfonic acid, and the like.
The reaction temperature is from -40.degree. C. to the boiling point of the
solvent used, preferably from room temperature to the boiling point of the
solvent.
The compound wherein R.sup.1 is an acyl group or which has an acyloxy group
at the 4 position of the naphthalene ring can be prepared, for example,
according to the following procedure.
##STR15##
(wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.1', m and n
have, respectively, the same meanings as defined before).
More particularly, the naphthol derivatives (IX) are reacted by a usual
manner with an acylating agent including, for example, a reactive acid
derivative such as acetic anhydride, a desired carboxylic acid or an acid
halide, or a carboxylic anhydride and a de-acidifying agent such as
pyridine at a temperature of from about 0.degree. C. to the boiling point
of the solvent used, thereby readily obtaining trans-acyloxy derivatives
of the general formula (VIII) which are one of the intended substances. A
trans or cis-form product may be obtained depending on the type of
substituent and, generally, trans-form products are obtained. For
obtaining cis-form products, light from a high pressure mercury lamp using
a Pyrex filter is irradiated on the trans-form products, thereby obtaining
cis-acyloxy derivatives.
The sensitizers for the reaction include acetone, propiophenone,
acetophenone, benzophenone, triphenylene, 2-acetonaphthone, 1-naphthyl
phenyl ketone, 1-acetonaphthone and the like.
The solvents for the reaction include alcohols such as methanol, ethanol
and the like, ketones such as acetone, methyl ethyl ketone, benzophenone
and the like, benzene, acetonitrile, and the like.
The reaction temperature is from -78.degree. C. to 40.degree. C.,
preferably from about 0.degree. C. to 30.degree. C.
The compound of the general formula (II) which is the starting material for
the preparation of the compounds of the invention is a novel compound and
is useful as an important intermediate for the preparation of the
naphthalene derivatives of the invention having good efficacy as
medicines.
Preparation Process A of Starting Substances
The compound (XIV) of the general formula (II) or (X) used as the starting
substance in the above preparation process can be prepared according to
the following procedure
##STR16##
(wherein R.sup.2, R.sup.3, R.sup.6, m and n have, respectively, the same
meanings as defined before, Z represents a group represented by R.sup.1,
and Y represents a protective group for the hydroxyl group).
More particularly, the aldehyde derivative of the general formula (XII) and
the organic metal compound of the general formula (XI) are reacted to
obtain an alcohol derivative of the general formula (XIII).
The organic metal compounds are, for example, alkyl lithium, Grignard
reagents, and the like.
The reaction is effected in a solvent selected, for example, from ether,
tetrahydrofuran, dioxane, pentane, hexane and the like.
The reaction temperature is from -78.degree. C. to 60.degree. C.,
preferably from -78.degree. C. to room temperature.
The alcohol derivative (XIII) thus obtained is oxidized by a usual manner
to obtain a ketone derivative of the general formula (XIV).
The oxidizing agents include, for example, manganese dioxide, chromic acid,
permanganates, lead tetraacetate, a halogen, N-halocarboxylic acid amides,
dimethylsulfoxide and the like.
The solvents for the reaction include, for example, water and alcohols such
as methanol, ethanol and the like, acetone, ether, acetonitrile, benzene,
dichloromethane, chloroform, ethyl acetate, pyridine, and the like.
The reaction temperature is selected from the range of from ice-cooling
conditions to the boiling point of the solvent used.
Preparation Process B of Starting Substances
For the preparation of the compounds of the general formula (XIV), in the
above preparation process A, wherein the protective group for the hydroxyl
group is a methoxymethyl group, m is equal to 1, and R.sup.2 is a lower
alkoxy group, they can be prepared according to the following procedure.
##STR17##
(wherein R.sup.6 and n have, respectively, the meanings as defined before,
and R.sup.10 represents a lower alkyl group).
More particularly, the compound of the general formula (XV) and a strong
base such as, for example, n-butyl lithium, are reacted, followed by
further reaction with N,N-dimethylformamide to obtain aldehyde derivative
(XVI). For the reaction, ethers such as ether, tetrahydrofuran and the
like are used as the solvent and the reaction is carried out at a
temperature of from -78.degree. C. to 80.degree. C., preferably from
-80.degree. C. to room temperature.
The aldehyde derivative (XVI) thus obtained is oxidized with an oxidizing
agent such as, for example, hydrogen peroxide, peracetic acid,
m-chloroperbenzoic acid or the like, thereby obtaining a formyl ester
derivative (XVII). Water, dichloromethane, chloroform, acetic acid and the
like are properly selected as the solvent.
The formyl ester derivative (XVII) thus obtained is subjected to alkali
hydrolysis by a usual manner to obtain naphthol derivative (XVIII).
The naphthol derivative (XVIII) thus obtained is interacted with an alkyl
halide by using a base including an alkali metal carbonate such as sodium
carbonate, potassium carbonate or the like, or an alkali metal halide such
as sodium hydride, to obtain alkoxynaphthalene (XIX). The halogen is
chlorine, bromine or iodine. The solvent is, for example, a ketone such as
acetone, methyl ethyl ketone or the like, N,N-dimethylformamide,
dimethylsulfoxide or the like.
The alkoxynaphthalene derivative (XIX) thus obtained is subjected to acid
hydrolysis by a usual manner using, for example, hydrochloric acid,
sulfuric acid, p-toluenesulfonic acid or the like, thereby obtaining
naphthol derivative (XX).
The naphthol derivative (XX) thus obtained is subsequently reacted, for
example, with an ortho ether derivative such as ethyl orthoformate or
methyl orthoformate, or dichloromethyl methyl ether to obtain the
hydroxyformyl derivative of the general formula (XXI). The catalyst for
the reaction includes, aluminum chloride, titanium tetrachloride or the
like. Dichloromethane, chloroform and the like are used as the solvent.
The formyl derivative (XXI) thus obtained is reacted by a usual manner with
chloromethyl methyl ether by the use of a base such as, for example,
sodium hydride, diisopropylethylamine or the like, there by obtaining
formyl derivative (XXII). The solvent is dichloromethane, chloroform,
ether, tetrahydrofuran or the like compound which does not take part in
the reaction. The reaction temperature if from -40.degree. C. to
60.degree. C., preferably from about 0.degree. C. to room temperature.
Preparation Process C of Starting Substances
The compound (XXII) may be prepared according to the following procedure.
##STR18##
(wherein R.sup.6, R.sup.10 and n have, respectively, the same meanings as
defined before).
More particularly, The naphthalene derivative of the general formula
(XXIII) is subjected to formylation, oxidation, hydrolysis and alkylation
according to a procedure similar to the preparation process B to obtain
the naphthalene derivative of the general formula (XXVII).
The naphthalene derivative (XXVII) thus obtained is subjected to
elimination of the protective group, for example, with
tetra-n-butylammonium fluoride to obtain an alcohol product (XXVIII).
The alcohol product (XXVIII) thus obtained is oxidized to obtain the
aldehyde derivative of the general formula (XXII).
As the oxidizing agent, there are mentioned manganese dioxide, chromic
acid, permanganates, lead tetraacetate, halogens, N-halocarboxylic acid
amides, dimethylsulfoxide and the like.
The solvent for the reaction includes, for example, water and alcohols such
as methanol, ethanol and the like, acetone, ether, acetonitrile, benzene,
dichloromethane, chloroform, ethyl acetate, pyridine, and the like.
The reaction temperature is appropriately selected from the range of from
an ice-cooling condition to the boiling point of the solvent used.
Preparation Process D of Starting Substances
The compound (XXIII) used in the preparation process C can be prepared, for
example, according to the following procedure.
##STR19##
(wherein R.sup.6 and n have, respectively, the same meanings as defined
before).
In the above reaction sequence, the naphthol derivative of the general
formula (XXIX) is reacted, for example, with an ortho-ester derivative
such as methyl orthoformate or ethyl orthoformate, or dichloromethyl
methyl ether, to obtain the hydroxyaldehyde derivative (XXX). Aluminum
chloride, titanium tetrachloride or the like is used as the catalyst. The
solvent for the reaction is, for example, dichloromethane, chloroform or
the like.
The hydroxyaldehyde derivative (XXX) is reacted, by a usual manner, with
chloromethyl methyl ether or the like by the use of a base such as, for
example, sodium hydride, diisopropylethylamine or the like, thereby
obtaining the aldehyde derivative (XXXI).
The aldehyde derivative (XXXI) thus obtained is reacted, by a usual manner,
with a reducing agent such as, for example, sodium borohydride, lithium
aluminium hydride or the like, thereby obtaining the alcohol derivative
(XXXII).
The alcohol derivative derivative (XXXII) thus obtained is reacted, by a
usual manner, with t-butylchlorodimethylsilane or the like by using a base
such as, for example, imidazole, triethylamine or the like, to obtain the
naphthalene derivative of the general formula (XXIII).
Preparation Process E of Starting Substances
As for the compound (XV) which has been used as the starting substance in
the preparation process B and wherein n is equal to 1 and R.sup.6 is a
lower alkyl group joined at the 5 position, one of specific preparation
procedures is illustrated below.
##STR20##
(wherein R.sup.11 represents a lower alkyl group).
More particularly, 1,8-naphthalenecarbolactone (XXXIII) is reacted with an
alkylating agent such as, for example, an alkyl lithium, a Grignard
reagent or the like to obtain the ketone derivative (XXXIV). The solvent
for the reaction is, for example, ether, tetrahydrofuran, hexane or the
like. The reaction temperature is from -90.degree. to 60.degree. C.,
preferably from -80.degree. to 0.degree. C.
The ketone derivative (XXXIV) thus obtained is reduced, by a usual manner,
with a reducing agent such as, for example, sodium borohydride, aluminum
hydride or the like to obtain the diol derivative (XXXV).
The thus obtained diol derivative (XXXV) is reacted, by a usual manner,
with fluoroacetic acid by the use of a de-acidifying agent such as, for
example, pyridine, at a temperature of an ice-cooling condition to room
temperature, thereby obtaining the trifluoroacetate (XXXVI).
The trifluoroacetate (XXXVI) thus obtained is catalytically hydrogenated by
the use of a catalyst such as, for example, palladium-carbon, thereby
obtaining the naphthol derivative (XXXVII). The solvent for the reaction
is, for example, alcohols such as methanol, ethanol and the like, ethyl
acetate, tetrahydrofuran or the like. Room temperature may be used for the
reaction.
The naphthol derivative (XXXVII) thus obtained is reacted, by a usual
manner, with chloromethyl methyl ether by the use of a de-acidifying agent
such as diisopropylethylamine, thereby obtaining the naphthol derivative
(XXXVIII).
Preparation Process F of Starting Substances
One of preparation processes of the compound (XV), used as the starting
substance in the above preparation process, wherein n is equal to 1 and
R.sup.6 a lower alkyl group branched at the 5 position is described below.
##STR21##
More particularly, 1,8-naphthalenecarbolactone (XXXIII) is reaction with a
Grignard reagent such as, for example, methyl magnesium bromide to obtain
the diol derivative (XXXIX). The solvent for the reaction is, for example,
ether, tetrahydrofuran or the like. The reaction temperature is from
-70.degree. C. to the boiling point of the solvent used, preferably from
-60 .degree. C. to 0.degree. C.
The thus obtained diol derivative (XXXIX) is heated by a usual manner along
with acetic anhydride in pyridine used as a solvent at a temperature of
from room temperature to 60.degree. C. to obtain the acetate (XXXX).
The acetate (XXXX) thus obtained is catalytically hydrogenated by the use
of a catalyst such as, for example, palladium-carbon to obtain reduced
product (XXXXI). The solvent for the reaction is, for example, alcohols
such as methanol, ethanol and the like, ethyl acetate, tetrahydrofuran or
the like. The reaction can proceed particularly at room temperature.
The reduced product (XXXXI) thus obtained is hydrolyzed as usual to obtain
the naphthol derivative (XXXXII).
The naphthol derivative (XXXXII) thus obtained is reacted, by a usual
manner, with chloromethyl methyl ether by the use of a de-acidifying agent
such as, for example, sodium hydride, diisopropylethylamine or the like,
thereby obtaining the naphthalene derivative (XXXXIII).
Preparation Process G of Starting Substances
The compound (XII) which has been used as the starting substance in the
preparation process A and wherein n is equal to 1, R.sup.6 is a lower
alkyl group at the 5 position, Z is an acetyl group, m is equal to 1, and
R.sup.2 is a lower alkyl group at the 3 position can also be prepared by
the following procedure.
##STR22##
(wherein R.sup.14 represents a lower alkyl group, R.sup.15, R.sup.16,
R.sup.17 and R.sup.18 may be the same or different and represent a
hydrogen atom or a lower alkyl group, and Ac has the same meaning as
defined before).
More particularly, the ester derivative of the general formula (XXXXIV) is
reacted as usual at 140.degree. C. in the presence of an aluminum chloride
catalyst to obtain the ketone product of the general formula (XXXXV).
Subsequently, the ketone product (XXXXV) is reacted with a benzyl halide
such as benzyl chloride by the use of a de-acidifying agent such as, for
example, sodium hydride, diisopropylethylamine or the like, thereby
obtaining the benzyl ether derivative (XXXXVI). The solvent for the
reaction is, for example, ethers such as ether, tetrahydrofuran and the
like, halogenated hydrocarbons such as dichloromethane, chloroform and the
like, benzene, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate or
the like. The reaction temperature is appropriately selected depending on
the type of reaction reagent.
The benzyl ether derivative (XXXXVI) thus obtained is reacted with an
alkylating agent such as an alkyl lithium or a Grignard reagent to obtain
the alcohol product (XXXXVII).
The alcohol product (XXXXVII) is heated as usual by the use of an acid
catalyst such as, for example, a hydrochloric acid aqueous solution for
dehydration reaction to obtain an olefin product (XXXXVIII) or (XXXXIX).
The olefin product (XXXXVIII) or (XXXXIX) thus obtained is subjected to
catalytic hydrogenation using a catalyst such as, for example,
palladium-carbon by a usual manner to obtain the naphthol derivative
(XXXXX). The solvent for the reaction is alcohols such as methanol,
ethanol and the like, ethyl acetate, tetrahydrofuran or the like. The
reaction may be carried out particularly at room temperature.
The naphthol derivative (XXXX) thus obtained is reacted with an ortho ester
such as methyl orthoformate or ethyl orthoformate, dichloromethyl methyl
ether or the like to obtain the hydroxyaldehyde derivative (XXXXXI).
As the catalyst, there is mentioned aluminum chloride, titanium
tetrachloride or the like. The solvent for the reaction is, for example,
dichloromethane, chloroform or the like.
The hydroxyaldehyde derivative (XXXXXI) thus obtained is reacted, as usual,
with an acylating agent such as acetic anhydride, acetyl chloride or the
like by the use of a de-acidifying agent such as, for example, pyridine,
triethylamine or the like, thereby obtaining the acetate (XXXXXII).
Preparation Process H of Starting Substances
The compound (XII) which has been used as the starting substance in the
preparation process A and wherein Z is a methoxymethyl group, m is equal
to 1, R.sup.2 is a halogen atom at the 3 position of the naphthalene ring,
n is equal to 1 and R.sup.6 is at the 5 position of the naphthalene ring
can be prepared according to the following procedure.
##STR23##
More particularly, the hydroxyaldehyde derivative (XXXXXIII) is reacted
with a halogenating agent such as, for example, sulfuryl chloride, bromine
or the like to obtain the halide (XXXXXIV).
The halide (XXXXXIV) thus obtained is reacted, as usual, with chloromethyl
methyl ether by the use of a de-acidifying agent such as, for example,
sodium hydride, diisopropylethylamine or the like to obtain the aldehyde
derivative of the general formula (XXXXXV).
Production process for starting material I
An example or a production process is described below for the compound (XV)
used as the starting material in the production process B described above
in which R.sup.6 is a lower alkoxyalkyl group.
##STR24##
where R.sup.20, R.sup.21 and R.sup.22 each represents a lower alkyl group
and X represents a halogen atom.
8-hydroxymethyl-1-naphthol (XXXXXVI) is reacted with chloromethyl methyl
ether in a customary manner, for example, by using potassium carbonate as
an acid remover to obtain a naphthalene derivative (XXXXXVII).
The resultant naphthalene derivative (XXXXXVII) is reacted with an
oxidizing agent, for example, pyridinium dichromate or pyridinium
chlorochromate to obtain an aldehyde derivative (XXXXXVIII). The reaction
can be conducted using dichloromethane as a reaction solvent at a room
temperature.
The resultant aldehyde (XXXXXVIII) is subjected in a customary manner to a
Wittig reaction with a phosphate ester (XXXXXIX) to obtain an unsaturated
ester derivative (XXXXXX).
The resultant unsaturated ester derivative (XXXXXX) is catalytically
hydrogenated by using a catalyst, for example, palladium carbonate to
obtain a naphthalene derivative (XXXXXXI). As a reaction solvent,
tetrahydrofuran, ethyl acetate, etc. may be used. Specifically, the
reaction can be conducted in a hydrogen atmosphere under 1 atm at a room
temperature.
The resultant naphthalene derivative (XXXXXXI) is reduced by using a
reducing agent, for example, aluminum lithium hydride to obtain an alcohol
(XXXXXXII).
The resultant alcohol (XXXXXXII) is reacted by a customary manner with a
halogenated alkyl (XXXXXXIII) by using a base, for example, sodium
hydride, potassium t-butoxide, etc. to obtain an aimed naphthalene
derivative (XXXXXZV).
Production process for the starting material J
One of starting material, naphthalene derivative (XXXXXXVII) for the
production process B can be produced by the following method:
##STR25##
where R.sup.6, X, n have the same meanings as described above.
That is, halogenated naphthol derivative (XXXXXXV) can be reacted in a
customary manner with a base, for example, sodium hydride or diisopropyl
ethylamine, with chloromethyl methyl ether to obtain an naphthol
derivative (XXXXXXVI).
The resultant naphthol derivative (XXXXXXVI) is reacted with a strong base
and, subsequently, treated with an appropriate halogenated alkyl to obtain
an alkylated naphthaol derivative (XXXXXXVII). Specifically, the reaction
is carried out using n-butyl lithium as a strong base, ethers such as
ether or tetrahydrofuran as a solvent at a reaction temperature from
-78.degree. C. to 30.degree. C., preferably, -78.degree. C. to -30.degree.
C.
Production process for starting material K
Naphthalene carbaldehyde derivative (XXXXXXXII) as one of the starting
materials for the Production Process C can be produced by the following
method.
##STR26##
where R.sup.6, R.sup.10 and n have the same meanings as described above.
That is, an aldehyde represented by the general formula (XXXXXXVIII) is
treated with hydrogen peroxide or a peracid such as peracetic acid or
n-fluoro perbenzoic acid to obtain a formic acid ester derivative
(XXXXXXIX). The reaction solvent can properly be selected from water,
dichloromethane, chloroform, acetic acid, etc.
The resultant formic acid ester derivative (XXXXXXIX) is alkali-hydrolized
by a customary method to obtain s naphthol derivative (XXXXXXX).
The resultant naphthol derivative (XXXXXXX) is reacted with an ortho-ester
derivative such as ethyl o-formate or methyl o-formate or dichloromethyl
methyl ether to obtain a hydroxyaldehyde derivative (XXXXXXXI). It is
possible to properly select aluminum chloride, titanium tetrachloride,
etc. as the catalyst, and dichloromethane, chloroform, etc. as the solvent
for the reaction.
The resultant hydroxyaldehyde derivative (XXXXXXXI) can be reacted with
chloromethyl methyl ether using a base, for example, sodium hydride,
diisopropyl ethylamine to obtain a naphthalene carbaldehyde derivative
(XXXXXXXII).
In order to describe the effects of the invention in more detail,
pharmacological experimental examples of typical compounds of the
invention are illustrated below.
Experimental Example
Inhibiting Action Against Production of Interleukin-1 (IL-1) from Human
Peripheral Blood Monocytes
Venous blood was taken out from healthy male volunteers in the presence of
citric acid. Mononuclear cells were obtained from the blood by the
Ficoll/Paque specific gravity centrifugal method. After washing the cells
three times with Hank's balanced salt solution, they were suspended in an
RPMI 1640 culture solution containing 10% of an heat-inactivated autoserum
at 2 to 3.times.10.sup.6 cells/ml. The resulting all suspension was places
in a 48-hole plate at 0.5 ml per hole and cultured at 37.degree. C. in 5%
CO.sub.2 /95% air for 2 hours. The culture plates was gently washed three
times with RPMI 1640 to remove non-adherent cells therefrom, after which
adherent cells were provided as monocytes for the following experiments.
Substances to be tested were each dissolved in ethanol and added to a
medium so that the final concentration of ethanol was 0.1%. After the
pre-incubation of thirty minutes, lipopolysaccharide was added at a final
concentration of 1 .mu.g/ml, followed by cultivation at 37.degree. C., in
5% CO.sub.2 /95% air for 18 hours.
After completion of the cultivation, the supernatant of the culture
solution was passed through a milli-pore filter for use as a measuring
sample of extracellular IL-1. The culture solution was freshly added to
the adherent cells and the cells were homogenized by sonication, followed
by passing through a milli-pore filter for use as a measuring sample of
intracellular IL-1.
It will be noted that the quantitative determination of IL-1 was made
according to the following procedure.
Quantitative Determination of IL-1
The quantitative determination of IL-1 was made according to a usual method
wherein thymocytes of C3H/HeJ mice were used and the growth reaction with
IL-1 in the presence of 1 .mu.l/mL of phytohemagglutinin (made by Difco
Inc.) was carried out as an index to incorporation of [.sup.3
H]-thymidine.
Reference IL-1 used was recombinant human IL-1.beta. (Genzyme Inc.) for
investigation of the production of IL-1 from human monocytes, and the
amount of IL-1 (Unit/ml) in the measuring sample was determined based on
the reference curve. The sum of extra- and intracellular IL-1 in each well
was calculated, and the IL-1 production inhibiting rate of the respective
substances to be tested was determined from comparison with the control.
The following data are added to Table 1.
59 in Example 33, 61 in Example 35, 51 in Example 36, 64 in Example 37 and
63 in Example 41.
TABLE 1
______________________________________
Inhibiting Percent of IL-1 Production
Compound No.
from Human Peripheral Blood Monocytes
(Example No.)
(3 .mu.M)
______________________________________
Compound 1
67
(Example 1)
Compound 2
52
(Example 2)
Compound 3
72
(Example 3)
Compound 5
65
(Example 5)
Compound 7
60
(Example 7)
Compound 8
55
(Example 8)
Compound 10
74
(Example 10)
Compound 11
85
(Example 11)
Compound 12
69
(Example 12)
Compound 14
79
(Example 14)
Compound 17
61
(Example 17)
Compound 19
74
(Example 19)
Compound 21
72
(Example 21)
Compound 23
58
(Example 23)
Compound 24
60
(Example 24)
Compound 29
57
(Example 29)
Compound 32
96
(Example 32)
______________________________________
From the results of the above experimental examples, it will be apparent
that the compounds of the invention have potent inhibiting action on
interleukin-1 production.
Moreover, the compounds of the invention have been found to suppress or
inhibit the production or release of cytokine represented by IL-1 or
various other inflammatory mediators, and these are useful as medicines
based on these actions.
The compounds of the invention are effective in curing or preventing
various autoimmune diseases including chronic articular rheumatism,
systematic lupus erythromatodes, systematic scleroderm, Bechet's disease,
periarteritis nodosa, ulcerative colitis, chronic active hepatitis,
glomerulonephritis and the like, and various intractable diseases based on
the morbid states of inflammatory symptoms such as arthritis deformans,
gout, atherosclerosis, psoriasis, atopic dermatitis, lung diseases
accompanied by granuloma and various encephalites.
Besides, the compounds are effective as curing and preventing medicines for
general symptoms such as the morbid states involving fever, rise in the
acute phase reactants or blood sedimentation ratio, and a certain type of
diabetes.
Since it has been suggested that IL-1, particularly IL-1.beta., is a
peptide causing hyperlagesia in the peripheral sites, the analgesic action
will be expected.
When the compounds of the invention are used as curing and preventing
medicines for these diseases, they may be orally dosed in the form of
tablets, powder, granules, capsules, syrup and the like, or may be
parenterally dosed in the form of a suppository, an injection, an endermic
liniment and drops. In the practice of the invention, it is preferred to
dose the compound as an oral agent.
The dosage may depend on the type of disease, the extent of symptom and the
age. When it is dosed to a human being as an oral agent, the dosage is
generally in the range of from 0.01 to 10 mg/kg, preferably from 0.01 to 2
mg/kg and more preferably from 0.1 to 1.5 mg/kg, which is dosed in one to
four times per day.
The preparation for the oral or parenteral administration is made by a
usual manner using ordinary pharmaceutically acceptable carriers.
Where injections or drops are prepared, pH adjusters, buffers, stabilizers,
plasticizers and the like may be added, if necessary, to the principal
ingredient and freeze-dried as required to make subcutaneous,
intramuscular or intravenous injections or drip injections.
EXAMPLES
Examples are described for further illustration of the compounds and the
preparation process of the invention, which should not be construed as
limiting the invention thereto.
Preparation processes of starting compounds used in the examples are
described as references.
Note) In NMR spectral data, any possible peaks of carboxylic acids may not
be detected.
Reference 1
8-Ethyl-1-methoxymethoxynaphthalene
##STR27##
(a) Preparation of 8-(1-hydroxyethyl)-1-naphthol
##STR28##
1040 g of 8'-hydroxy-1'-acetonaphthone was dissolved in 8.5 liters of
ethanol, to which 131 g of sodium borohydride was added while ice-cooling
in order not to allow the temperature of the reaction solution to exceed
30.degree. C. After agitation for 30 minutes at room temperature, excess
sodium borohydride was decomposed with 1 liter of acetone. The reaction
solution was concentrated under reduced pressure, after which 4 liters of
1N hydrochloric acid was added, followed by extraction with ethyl acetate.
The resultant organic phase was washed with a saturated saline solution to
remove the excess acid. After drying with anhydrous magnesium sulfate, the
solvent was distilled off and a small amount of hexane was added to the
resultant residue for crystallization. The crystals were collected by
filtration to obtain 1000 g of the captioned compound as light brown
crystals.
Melting point: 89.degree.-90.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.84 (d,J=7.2 Hz,3H),
3.7(br.s,1H), 5.31(q,J=7.2 Hz,1H), 6.94-7.83(m,6H), 10.40(Br.s,1H)
(b) Preparation of 7-ethyl-1-methoxymethoxynaphthalene
##STR29##
270 g of 8-(1-hydroxyethyl)-1-naphthol was dissolved in 500 ml of
tetrahydrofuran and 170 ml of pyridine, followed by dropping 357 g of
anhydrous trifluoroacetic acid under ice-cooling conditions in 45 minutes.
The reaction solution was agitated under ice-cooling conditions for 0.5
hours, after which 2 liters of ethyl acetate was added. After washing with
a saturated saline solution, 1N hydrochloric acid, a saturated saline
solution and a sodium hydrogencarbonate saturated aqueous solution in this
order, the reaction solution was dried with anhydrous magnesium sulfate.
Insoluble matters were removed by filtration and 3.75 liters of
tetrahydrofuran was added to the resultant filtrate. 37.5 g of 10%
palladium-carbon (water content:50%) was further added, followed by
violent agitation in an atmosphere of hydrogen at 1 atm., for 6 hours.
After removal of the palladium-carbon by filtration, the filtrate was
concentrated to half in volume. The resultant residue was added under
agitation to a saturated sodium hydrogencarbonate aqueous solution,
followed by extraction with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution. After drying with anhydrous
magnesium sulfate, the solvent was distilled off and the resultant residue
was dissolved in 1 liter of N,N-dimethylformamide. 69 g of 60% sodium
hydride was gently added to the solution under ice-cooling conditions,
followed by agitation for further 20 minutes. 160 g of chloromethyl methyl
ether was dropped in the resultant reaction solution so that the inner
temperature did not exceed 20.degree. C. After further agitation at room
temperature for 30 minutes, the reaction solution was poured into iced
water and extracted with ethyl acetate. The organic phase was washed with
a saturated saline solution and dried with anhydrous magnesium sulfate.
The solvent was distilled off, followed by purification by silica gel
column chromatography (hexane), thereby obtaining 259 g of the captioned
compound as a light yellow oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.30 (d,J=7 Hz,3H), 3.28(q,J=7
Hz,2H), 3.46(s,3H), 5.24(s,2H), 6.90-7.60(m,6H)
Reference 2
1-Methoxy-8-propylnaphthalene
##STR30##
(a) Preparation of 8'-hydroxy-1'-propiononaphthone
##STR31##
460 g of 1,8-naphthalenecarbolactone was dissolved in 4.2 liters of
tetrahydrofuran in a stream of nitrogen and cooled down to -78.degree. C.
900 ml of a diethyl ether solution of 3M ethylmagnesium bromide was
dropped in the solution so that the temperature was maintained at
-40.degree. C. to -50.degree. C. After the dropping, the solution was
returned gently to room temperature. Again, the solution was cooled down
to 0.degree. C., to which a saturated ammonium chloride aqueous solution
was added, followed by extraction with ethyl acetate. After washing the
resultant organic phase with a saturated saline solution, it was dried
with anhydrous magnesium sulfate and concentrated under reduced pressure.
The resultant residue was purified by silica gel column chromatography
(15% ethyl acetate/hexane) to obtain 176 g of the captioned compound as
yellow needle crystals.
Melting point: 114.degree.-117.degree. C. .sup.1 H-NMR (90 MHz,
CDCl.sub.3).delta.: 1.21 (t,J=7 Hz,3H), 3.00(q,J=7 Hz,2H), 7.92(dd,J=3.6
Hz, 6 Hz,1H), 7.12-7.68(m,4H), 7.82(dd,J=1.8 Hz,7 Hz,1H), 8.66(br.s,1H)
(b) Preparation of 8-(1-hydroxy-1-propyl)-1-naphthol
##STR32##
1270 g of 8'-hydroxy-1'-propiononaphthone was dissolved in 15 liters of
ethanol and cooled to 10.degree. C. on an ice bath. 143.9 g of sodium
borohydride was added to the solution at not higher than 30.degree. C.
After agitation for 30 minutes, 1 liter of acetone was gently added,
followed by removal of the solvent by distillation under reduced pressure.
The concentrated solution was added to 1N hydrochloric acid at 0.degree.
C. and extracted with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution to an extent of the pH of 6. It
was dried with anhydrous magnesium sulfate and concentrated under reduced
pressure. Hexane was added to the resultant residue for crystallization,
followed by washing with hexane to obtain 1126 g of the captioned compound
as light brown crystals.
Melting point: 94.degree.-95.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 0.85(t,J=7 Hz,3H),
1.60-2.32(m,2H), 4.86(t,J=7 Hz,1H) 6.76-7.44(m,5H), 7.66(dd,J=3 Hz,7
Hz,1H)
(c) Preparation of 1-methoxymethoxy-8-propylnaphthalene
##STR33##
1.9 g of 8-(1-hydroxy-1-propyl)-1-naphthol was dissolved in 34 ml of
tetrahydrofuran, to which 8.2 ml of pyridine was added, followed by
cooling to 10.degree. C. on an ice bath. 4.4 ml of anhydrous
trifluoroacetic acid was added to the solution in 30 minutes, followed by
reaction at room temperature for 30 minutes. Ethyl acetate and water were
added to the reaction solution for extraction and the resultant organic
phase was washed with 1N hydrochloric acid, a saturated sodium
hydrogencarbonate aqueous solution and a saturated saline solution in this
order and dried with anhydrous magnesium sulfate. The insoluble matters
were removed by filtration and 0.38 g of 10% palladium-carbon (water
content of 50%) was added to the filtrate, followed by hydrogenation at
normal temperatures and pressures for 4 hours. After removal of the
palladium-carbon by filtration, the solution was concentrated under
reduced pressure to an extent of 1/3 of the total volume. The residual
solution was charged into a saturated sodium hydrogencarbonate aqueous
solution and extracted with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution and dried with anhydrous magnesium
sulfate, after which it was concentrated under reduced pressure to obtain
2.3 g of a residue as a brown oily substance. This was dissolved in 20 ml
of N,N-dimethylformamide without purification, to which 0.55 g of 804
sodium hydride was added at 0.degree. C. After reaction at room
temperature for 10 minutes, the solution was again cooled down to
0.degree. C., followed by addition of 1.43 ml of chloromethyl methyl
ether. After further reaction at room temperature for 1 hour, water was
added, followed by extraction with ethyl acetate. The resultant organic
phase was washed with a saturated saline solution, dried with anhydrous
magnesium sulfate and concentrated under reduced pressure. The resultant
residue was purified by silica gel column chromatography (24 ethyl
acetate/hexane) to obtain 1.9 g of the captioned compound as a brown oily
substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.02(t,J=7 Hz,3H),
1.40-1.96(m,2H), 3.12-3.36(m,2H) 3.53(s,3H), 5.31(s,2H), 6.98-7.68(m,6H)
Reference 3
5-Ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR34##
(a) Preparation of 8-ethyl-1-methoxymethoxy-2-naphthalenecarbaldehyde
##STR35##
300 g of 8-ethyl-1-methoxymethoxynaphthalene was dissolved in 2.2 liters of
absolute ether, in which 1.3 liters of a hexane solution of 1.6M n-butyl
lithium was gently dropped at -20.degree. C. in a stream of nitrogen.
After the dropping, the solution was raised to room temperature and
agitated for 2 hours. It was again cooled down to -40.degree. C., to which
215 ml of N,N-dimethylformamide was added. After agitation for 30 minutes,
100 ml of water was added and the resultant organic phase was washed with
a saturated saline solution. After drying with anhydrous magnesium
sulfate, the solvent was distilled off and the residue was purified by
silica gel column chromatography (5% ethyl acetate/hexane) to obtain 253 g
of the captioned compound as colorless crystals.
Melting point: 41.5.degree.-42.5.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.31(t,J=7 Hz,3H), 3.30(q,J=7
Hz,2H), 3.53(s,3H), 5.09(s,2H), 7.21-7.87(m,5H), 10.46(s,1H)
(b) preparation of 8-ethyl-2-methoxy-1-methoxy-methoxynaphthalene
##STR36##
220 g of 8-ethyl-1-methoxymethoxy-2-naphthalenecarbaldehyde was dissolved
in 1540 ml of dichloromethane, to which 186 g of 80 to 85%
m-chloroperbenzoic acid was added portion by portion. The reaction
solution generated heat and was gently refluxed. The reaction solution was
ice-cooled, to which 200 ml of a saturated sodium thiosulfate aqueous
solution was added. The precipitated insoluble matters were removed by
filtration and washed with dichloromethane. The filtrate was washed with a
saturated sodium hydrogencarbonate aqueous solution and a saturated saline
solution and dried with anhydrous magnesium sulfate. After removal of the
solvent by distillation, 254 g of the resultant residue was dissolved in
500 ml of methanol, to which 89 g of potassium hydroxide preliminarily
dissolved in 200 ml of water was added, followed by refluxing for 20
minutes. The reaction solution was poured into 700 mo of cooled 2N
hydrochloric acid and extracted with ethyl acetate. The resultant organic
phase was washed with a saturated saline solution and dried with anhydrous
magnesium sulfate, from which the solvent was distilled off. 278 g of the
resultant residue was dissolved in 600 ml of N,N-dimethylformamide, to
which 500 g of anhydrous potassium carbonate and 256 g of methyl iodide
were added, followed by agitation at 80.degree. C. for 2 hours. The
insoluble matters were filtered off and washed with ethyl acetate. Water
was added to the resultant filtrate, which was extracted with ethyl
acetate. The resultant organic phase was washed with a saturated saline
solution and dried with anhydrous magnesium sulfate. After removal of the
solvent by distillation, the resultant residue was purified by silica gel
column chromatography to obtain 166 g of the caption compound as a yellow
oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.32(t,J=7 Hz,3H), 3.36(q,J=7
Hz,2H), 3.58(s,3H), 3.95(s,3H), 5.16(s,2H), 7.16-7.70(m,5H)
(c) Preparation of 5-ethyl-4-hydroxy-3-methoxy-1-naphthalenecarbaldehyde
##STR37##
200 g of 8-ethyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 1
liter of acetone, to which dilute hydrochloric acid (concentrated
hydrochloric acid 81 ml/water 200 ml) was added under ice-cooling
conditions, after which the ice bath was removed, followed by agitation at
room temperature for 5 hours. The reaction solution was poured into iced
water and extracted with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution and dried with anhydrous magnesium
sulfate. After removal of the solvent by distillation, 178 g of the
resultant oily substance was dissolved in dichloromethane, to which 178 ml
of titanium tetrachloride was gently added under ice-cooling conditions.
After agitation for 30 minutes, 121 ml of dichloromethyl methyl ether was
gradually added and agitated for 30 minutes. Iced water was gently added
to the reaction solution, followed by extraction with ethyl acetate. The
resultant organic phase was washed with a saturated saline solution and
dried with anhydrous magnesium sulfate. After removal of the solvent by
distillation, the resultant residue was washed with a mixture of
hexane/isopropyl ether (1:1) to obtain 110 g of the caption compound as
yellowish brown crystals.
Melting point: 114.degree.-115.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.33(t,J=7 Hz,3H), 3.37(q,J=7
Hz,2H), 4.09(s,3H), 7.05(s,1H), 7.20-7.56(m,2H), 7.77(s,1H), 8.97(dd,J=1.6
Hz,8Hz,1H), 10.39(s,1H)
(d) Preparation of
5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR38##
324 g of 5-ethyl-4-hydroxy-3-methoxy-1-naphthalenecarbaldehyde was
dissolved in 1 liter of N,N-dimethylformaldehyde, to which 68 g of 60%
sodium hydride was gently added under ice-cooling conditions. After
agitation for 10 minutes, 128 ml of chloromethyl methyl ether was
gradually added so that the reaction temperature did not exceed 15.degree.
C. After agitation at room temperature for 20 minutes, the reaction
solution was poured into iced water and extracted with ethyl acetate. The
resultant organic phase was washed with a saturated saline solution and
dried with anhydrous magnesium sulfate. The solvent was distilled off and
the resultant residue was purified by silica gel column chromatography (5%
ethyl acetate/hexane) to obtain 288 g of the captioned compound as a brown
oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.30(t,J=7 Hz, 3H ), 3.36(q,J=7
Hz,2H), 3.55(s,3H), 4.00(s,3H), 5.31(s,2H), 7.20-7.50(m,2H), 7.76(s,1H),
8.90 (dd, J=2.6 Hz, 7 Hz, 1H), 10.36(s,1H)
Reference 4
3-Methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde
##STR39##
(a) Preparation of 1-methoxymethoxy-8-propyl-2-naphthalenecarbaldehyde
##STR40##
350 g of 1-methoxymethoxy-8-propylnaphthalene was dissolved in 3 liters of
absolute ether and cooled down to -35.degree. C. 1.43 liters of a hexane
solution of 1.6M n-butyl lithium was added to the solution at a
temperature not higher than -30.degree. C., followed by gradually raising
the temperature and reaction at room temperature for further 1 hour. The
reaction solution was again cooled down to -40.degree. C., to which 222 ml
of N,N-dimethylformamide was added in 15 minutes. The mixture was slowly
raised to 10.degree. C., to which water was added portion by portion,
followed by extraction with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution and dried with anhydrous magnesium
sulfate, after which it was concentrated under reduced pressure to obtain
460 g of a black reside. This residue was purified by silica gel column
chromatography (5% ethyl acetate/hexane) to obtain 326 of the captioned
compound as a brown oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 0.96(t,J=7 Hz,3H),
1.40-1.92(m,2H), 3.04-3.30(m,2H), 3.52(s,3H), 5.06(s,2H), 7.16-7.88(m,5H),
10.48(s,1H)
(b) Preparation of 2-methoxy-1-methoxymethoxy-8-propylnaphthalene
##STR41##
1.6 g of 1-methoxy-8-propyl-2-naphthalenecarbaldehyde was dissolved in 16
ml of dichloromethane, to which 1.6 g of 80 to 85% m-chloroperbenzoic acid
was add, followed by heating under reflux for 30 minutes. The reaction
solution was returned to room temperature and the organic phase (?) was
washed with a sodium thiosulfate aqueous solution, a saturated sodium
hydrogencarbonate aqueous solution and a saturated saline solution in this
order and dried with anhydrous magnesium sulfate. Thereafter, it was
concentrated under reduced pressure. 1.6 g of the resultant brown oily
residue was dissolved in 5.2 ml of methanol without purification, to which
a potassium hydroxide aqueous solution (potassium hydroxide 0.52g/water
5.2 ml) was added, followed by reaction at 60.degree. C. for 15 minutes.
The reaction solution was returned to room temperature and rendered acidic
by means of dilute hydrochloric acid, and was extracted with ethyl
acetate. The resultant organic phase was washed with a saturated sodium
hydrogencarbonate aqueous solution and a saturated saline solution in this
order and dried with anhydrous magnesium sulfate, after which it was
concentrated under reduced pressure. 1.5 g of the resultant black oily
residue was dissolved in 15 ml of N,N-dimethylformamide without
purification, to which g of methyl iodide and 4.6 g of anhydrous potassium
carbonate were added, followed by reaction at 80.degree. C. for 1 hour.
After removal of the solid matters by filtration, water was added,
followed by extraction with ethyl acetate. The organic phase was washed
with a saturated saline solution and dried with anhydrous magnesium
sulfate, after which it was concentrated under reduced pressure. The
resultant reside was purified by silica gel column chromatography (2%
ethyl acetate/hexane) to obtain 1.3 g of the captioned compound as a brown
oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 0.96(t,J=7HZ,3H), 1.68(m,2H),
3.08-3.40(m,2H), 3.56(s,3H), 3.92(s,3H), 5.14(s,2H), 7.06-7.26(m,3H),
7.38-7.62(m,2H)
(c) Preparation of 4-hydroxy-3-methoxy-5-propyl-1-naphthalenecarbaldehyde
##STR42##
206 g of 2-methoxy-1-methoxymethoxy-8-propylnaphthalene was dissolved in
1160 ml of acetone and cooled to 0.degree. C. Diluted hydrochloric acid
(concentrated hydrochloric acid 84 ml/water 206 ml) was added to the
solution in 15 minutes, which was returned to room temperature at which
the reaction was effected at 20.degree. C. for 5 hours, followed by
addition of water and extraction with ethyl acetate. The resultant organic
phase was washed with a saturated saline solution to neutrality, dried
with anhydrous magnesium sulfate, and concentrated under reduced pressure.
173 g of the resultant brown oily substance was dissolved in 1350 g of
dichloromethane without purification and cooled down to 0.degree. C. 176.3
ml of titanium tetrachloride was dropped in the solution at 5.degree. C.
or below, to which 114.3 ml of dichloromethyl methyl ether was added at
5.degree. C. or below at which the reaction was carried out for 10
minutes. The reaction solution was slowly added to iced water and
extracted with ethyl acetate. The resultant organic phase was washed with
a a saturated sodium hydrogencarbonate aqueous solution and a saturated
saline solution in this order and dried with anhydrous magnesium sulfate,
and was concentrated under reduced pressure. The resultant crystals were
washed with a 30% isopropyl ether/hexane solution to obtain 103 g of the
captioned compound as yellowish brown crystals.
Melting point: 128.degree.-129.degree. C. .sup.1 H-NMR (90 MHz,
CDCl.sub.3).delta.: 1.00(t,J=7 Hz,3H), 1.46-1.92(m,2H), 3.14-3.36(m,2H),
4.06(s,3H), 7.16-7.54(m,2H), 7.74(s,1H), 8.96(dd,J=1.8 Hz,9 Hz,1H),
10.38(s,1H)
(d) Preparation of
3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde
##STR43##
322 g of 4-hydroxy-3-methoxy-5-propyl-1-naphthalenecarbaldehyde was
dissolved in 1.3 liters of N,N-dimethylformamide and cooled to 10.degree.
C. 63.3 g of 60% sodium hydride was added to the solution at 30.degree. C.
or below and agitated for 20 minutes. The reaction solution was cooled to
5.degree. C., to which 190 ml of chloromethyl methyl ether was added.
After agitation at room temperature for 2 hours, the solution was poured
into iced water and extracted with ethyl acetate. The resultant organic
phase was washed with a saturated saline solution, after which it was
dried with anhydrous magnesium sulfate and concentrated under reduced
pressure. The resultant residue was purified by silica gel column
chromatography (10% ethyl acetate/hexane) to obtain 294.5 g of the
captioned compound as a brown oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.96(t,J=7 Hz,3H),
1.42-1.90(m,2H), 3.12-3.42(m,2H), 3.54(s,3H), 4.00(s,3H), 5.28(s,2H),
7.14-7.48(m,2H), 7.76(s,1H), 8.99(dd,J=1.8 Hz,7 Hz,1H), 10.45(s,1H)
Reference 5
3-Ethoxy-5-ethyl-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR44##
In Reference 3(b), ethyl iodide was used instead of methyl iodide, followed
by the procedures of References 3(c) and 3(d), thereby obtaining the
captioned compound as a yellowish brown oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.28(t,J=7.7 Hz,3H), 1.50(t,J=7.7
Hz,2H), 3.36(q,J=7.7 Hz,2H), 3.52(s,3H), 4.20(q,J=7.7 Hz,2H), 5.32(s,2H),
7.18-7.48(m,2H), 7.72(s,1H), 8.88(dd,J=2.6 Hz,7.7 Hz,1H), 10.30(s,1H)
Reference 6
5'-Ethyl-3'-methoxy-4'-methoxymethoxy-1'-acetonaphthone
##STR45##
2 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was
dissolved in 20 ml of absolute tetrahydrofuran, to which 11.5 ml of an
ethyl solution of 1.12M methyl lithium was added at -78.degree. C. After
30 minutes, an ammonium chloride aqueous solution was added to the
solution and extracted with ethyl acetate. The resultant organic phase was
dried with anhydrous magnesium sulfate and the solvent was distilled off
to obtain 2.1 g of a brown oily substance. This substance was dissolved in
20 ml of dichloromethane without isolation and purification, to which 30 g
of manganese dioxide was added, followed by agitation at room temperature
for 20 hours. The insoluble matters were removed by filtration and the
filtrate was concentrated, followed by purification by silica gel column
chromatography (10% ethyl acetate/hexane) to obtain 1.3 g of the captioned
compound as a yellow oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.27(t,J=7 Hz,3H), 2.70(s,3H),
3.34(q,J=7.5 Hz,2H), 3.53(s,3H), 3.96(s,3H), 5.21(s,2H), 7.20-7.31(m,2H),
8.21-8.37(m,1H)
Reference 7
5'-Ethyl-3'-methoxy-4'-methoxymethoxy-1'-valeronaphthone
##STR46##
5-Ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde and a hexane
solution of 1.6M n-butyl lithium were used and treated in the same manner
as in Reference 6 to obtain the captioned compound as a yellow oily
substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.80-1.60(m,3H), 1.12-1.92(m,7H),
2.96(t,J=7 Hz,2H) 3.34(q,J=7 Hz,2H) 3.54(s,3H), 3.96(s,3H), 5.18(s,2H),
7.16-7.32(m,2H) 7.42(s,1H), 7.92-8.10(m,1H)
Reference 8
1-(t-Butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene
##STR47##
(a) Preparation of 4-hydroxy-5-methyl-1-naphthalenecarbaldehyde
##STR48##
101.9 g of 8-methyl-1-naphthol was dissolved in 815 ml of dichloromethane,
in which 141.8 ml of titanium tetrachloride was gradually dropped under
ice-cooling conditions. Thereafter, 93.7 ml of dichloromethyl methyl ether
was gradually dropped under ice-cooling conditions. After agitation for 10
minutes, 200 ml of water was gently dropped under ice-cooling conditions.
The reaction solution was extracted with ethyl acetate and the resultant
organic phase was washed with water. After drying with anhydrous magnesium
sulfate, the solvent was distilled off and the resultant crystals were
washed with chloroform to obtain 80 g of the captioned compound as brown
crystals.
Melting point: 208.degree. C. (decomposed)
.sup.1 H-NMR(90 MHz, DMSO-d.sub.6).delta.: 2.88(s,8H), 6.98(d,J=7 Hz,1H),
7.10-7.60(m,2H), 7,84(d,J=7 Hz,1H), 9.06(br.d,J=7 Hz,1H), 10.02(s,1H)
11.24(s,1H)
(b) Preparation of 4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde
##STR49##
18 g of 4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 15 g of
N,N-diisopropylethylamine were dissolved in 200 ml of dichloromethane, in
which 9.3 g of chloromethyl methyl ether was gradually dropped under
ice-cooling conditions. After agitation at room temperature overnight, the
reaction solution was washed with water and dried with anhydrous magnesium
sulfate. The solvent was distilled off and the residue was purified by
silica gel column chromatography (10% ethyl acetate/hexane) to obtain 16.8
g of the captioned compound as light brown crystals.
Melting point: 42.degree.-43.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.90(s,3H), 3.54(s,3H),
5.36(s,3H), 7.06(d,J=7.7 Hz,1H), 7.20-7.56(m,2H), 7,78(d,J=7.7 Hz,1H),
9.16(br.d,J=7.7 Hz,1H), 10.10(s,1H)
(c) Preparation of 1-hydroxymethyl-4-methoxymethoxy-5-methylnaphthalene
##STR50##
1.23 g of sodium borohydride was added to an ethanol (100 ml) solution of
15 g of 4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde at room
temperature and agitated for 30 minutes. Water was added to the reaction
solution and the resultant crystals were collected by filtration and dried
to obtain 14 g of the captioned compound as light brown crystals.
Melting point: 91.degree.-93.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.78(br.t,J=5Hz,1H), 2.91(s,3H),
3.51(s,3H), 4.96(br,d, J=5 Hz,2H), 5.26(s,2H), 6.92(d,J=7 Hz,1H),
7.10-7.42 (m,3H), 7.87(m,1H)
(d) Preparation of
1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene
##STR51##
13.7 g of t-butylchlorodimethylsilane was added to an
N,N-dimethylaminopyridine (100 ml) solution of 14 g of
1-hydroxymethyl-4-methoxymethoxy-5-methylnaphthalene, 6.64 g of imidazole,
and 0.4 g of 4-dimethylaminopyridine and agitated at room temperature
overnight. Water was added to the reaction solution, followed by
extraction with ethyl acetate. Thereafter, the resultant organic phase was
washed with water and then with a saturated saline solution. After drying
with anhydrous magnesium sulfate, the solvent was distilled off and the
residue was purified by silica gel column chromatography (5% ethyl
acetate/hexane) to obtain 19 g of the captioned compound as a light brown
oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.10(s,6H), 0.93(s,9H),
2.89(s,3H), 3.49(s,3H), 5.01(s, 2H), 5.25(s,2H), 6.95(d,J=7 Hz,1H),
7.06-7.40 (m,3H), 7.72(m,1H)
Reference 9
3-Methoxy-4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde
##STR52##
(a)
1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methyl-3-naphthalenec
arbaldehyde
##STR53##
52 ml of a hexane solution of 1.6M n-butyl lithium was dropped in an
absolute ether (110 ml) solution of 19 g of
1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene and
agitated for 1 hour. After ice cooling, 8.5 ml of N,N-dimethylformamide
was dropped in the reaction solution and the ice bath was removed,
followed by agitation for 1 hour until room temperature was reached. Iced
water was added to the reaction solution, followed by extraction with
ethyl acetate. The resultant organic phase was washed with a saturated
saline solution and dried with anhydrous magnesium sulfate. After removal
of the solvent by distillation, the residue was purified by silica gel
column chromatography (2% ethyl acetate/hexane) to obtain 14.1 g of the
captioned compound as a brown oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.11(s,6H), 0.93(s,9H),
2.89(s,3H), 3.51(S,3H), 5.04(s, 2H), 7.18-7.52(m,2H). 7.75-7.91(m,2H),
10.38(s,1H)
(b) Preparation of
1-(t-butyldimethylsilyl)oxymethyl-3-methoxy-4-methoxymethoxy-5-methylnapht
halene
##STR54##
10.8 g of 80 to 85% m-chloroperbenzoic acid was added to a dichloromethane
(130 ml) solution of 10 g of
1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methyl-3-naphthalenec
arbaldehyde and heated for 1 hour under reflux. The reaction solution was
washed with a sodium thiosulfate aqueous solution, after which it was
further washed with water, a saturated sodium hydrogencarbonate aqueous
solution and a saturated saline solution in this order and dried with
anhydrous magnesium sulfate, followed by removal of the solvent by
distillation. 9.3 g of the resultant brown oily substance and 2.1 g of
sodium hydride were suspended in 21 ml of methanol and 21 ml of water and
refluxed for 15 minutes. After cooling, the suspension was rendered acidic
by means of dilute hydrochloric acid, followed by extraction with ethyl
acetate. After washing with a saturated saline solution, the extract was
dried with anhydrous magnesium sulfate, from which the solvent was
distilled off. 5 ml of methyl iodide was added to an N,N-dimethylformamide
(100 ml) solution of 8.5 g of the resultant brown oily substance and 22.1
g of potassium carbonate, followed by reaction at 60.degree. to 70.degree.
C. for 1 hour. The insoluble matters were removed by filtration and the
resultant filtrate was diluted with ether. After washing with water, the
diluted filtrate was washed with a saturated saline solution and dried
with magnesium sulfate. After removal of the solvent by distillation, the
residue was purified by silica gel column chromatography (5% ethyl
acetate/hexane) to obtain 7.3 g of the captioned compound as a brown oily
substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.14(s,6H), 0.98(s,9H),
2.92(s,3H), 3.57(s,3H), 3.94(s, 3H), 5.11(s,4H), 7.10-7.66(m,4H)
(c) Preparation of
1-hydroxymethyl-3-methoxy-4-methoxymethoxy-5-methylnaphthalene
##STR55##
32 ml of a tetrahydrofuran solution of 1M tetra-n-butylammonium fluoride
was added to a tetrahydrofuran (150 ml) solution of 7.3 g of
1-(t-butyldimethylsilyl)oxymethyl-3-methoxy-4-methoxy-methoxy-5-methylnaph
thalene and agitated for 1 hour. Water was added to the reaction solution
and extracted with ethyl acetate, and the resultant organic phase was
washed with water and a saturated saline solution, followed by drying with
anhydrous magnesium sulfate and removal of the solvent by distillation to
obtain the captioned compound as an oily substance. This compound was used
for subsequent reaction without purification.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.28(s,1H), 2.92(s,3H),
3.56(s,3H), 3.88(s,3H), 5.01(s, 2H), 5.11(s,2H), 7.14-7.36(m,3H),
7.75(m,1H)
(d) Preparation of
3-methoxy-4-methoxymethoxy-5-methyl-1-naphthalenecarbaldehyde
##STR56##
37 g of manganese dioxide was added to a dichloromethane (150 ml) solution
of 1-hydroxymethyl-3-methoxy-4-methoxymethoxy-5-methylnaphthalene and
agitated at room temperature overnight. The reaction suspension was
filtered through Celite and the resultant filtrate was concentrated under
reduced pressure, followed by purification by silica gel column
chromatography (5% ethyl acetate/hexane) to obtain 3.8 g of the captioned
compound as light yellowish brown crystals.
Melting point: 48.degree.-50.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.94(s,3H), 3.55(s,3H),
3.99(s,3H), 5.29(s,2H), 7.18-7.48(m,2H), 7.77(s,1H9, 8.90(m,1H9,
10.43(s,1H)
Reference 10
3,5-Dimethoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR57##
4-Hydroxy-5-methoxy-1-naphthalenecarbaldehyde was treated in the same
manner as in References 8, 9 to obtain the captioned compound as a yellow
oily substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 3.66(s,3H), 3.97(s,3H),
4.01(s,3H), 5.20(s,2H), 6.90(m,1H), 7.42(t,J=2 Hz,1H), 7.80(s,1H),
8.66(m,1H)
Reference 11
8-Isopropyl-1-methoxymethoxynaphthalene
##STR58##
(a) Preparation of 8-(1-hydroxy-1-methyl-1ethyl)-1-naphthol
##STR59##
20.0 g of 1,8-naphthalenecarbolactone was dissolved in 200 ml of absolute
tetrahydrofuran and cooled down to -60.degree. C. In the solution was
dropped 140 ml of a diethyl ether solution of 3.0M methylmegnesium bromide
so that the inside of the system was -30.degree. C. or below. After
agitation at -30.degree. C. for 1 hour, a saturated ammonium chloride
aqueous solution was added, followed by extraction with ethyl acetate. The
resultant organic phase was dried with anhydrous magnesium sulfate and the
resulting filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (10% ethyl
acetate/hexane) to obtain 14.3 g of the captioned compound as white
crystals.
Melting point (.degree. C.):
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.81(s,6H), 6.91-7.42(m,5H),
7.66(dd,J=1.8 Hz, 7.7 Hz,1H)
(b) Preparation of 8-isopropenyl-1-naphthyl acetate
##STR60##
11.3 g of 8-(1-hydroxy-1-methyl-1-ethyl)-1-naphthol was dissolved in 24 ml
of pyridine, to which 12 ml of anhydrous acetic acid was added. The
solution was raised in temperature to 60.degree. C. and heated for 6 hours
under agitation. Water was added to the reaction solution, followed by
extraction with ethyl acetate. The resulting organic phase was washed with
a 2N hydrochloric acid aqueous solution, water and a saturated saline
solution in this order, dried with anhydrous magnesium sulfate, and
concentrated under reduced pressure. The resultant residue was purified by
silica gel column chromatography (10% ethyl acetate/hexane) to obtain 8.6
g of the captioned compound as an oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.16(t,J=0.6 Hz,3H), 2.27(s,3H),
4.81(m,1H), 5.06(m,1H), 6.98-7.80(m,6H)
(c) Preparation of 8-isopropyl-1-naphthyl acetate
##STR61##
3.6 g of 8-isopropenyl-1-naphthyl acetate was dissolved in 100 ml of
ethanol, to which 0.2 g of 10% palladium-carbon (water content of 50%) was
added, followed by hydrogenation at normal temperatures and normal
pressure for 20 hours. After removal of the palladium-carbon by
filtration, the resulting filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (3%
ethyl acetate/hexane) to obtain 1.72 g of the captioned compound as an
oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.36(d,J=6.7 Hz,6H), 2.40(s,3H,
3.85-4.16(m,1H), 7.0-7.8(m,6H)
(d) Preparation of 8-isopropyl-1-methoxymethoxy naphthalene
##STR62##
8.40 g of 8-isopropyl-1-naphthyl acetate was dissolved in 50 ml of
methanol, to which 2.2 g of sodium methoxide was added at room
temperature, followed by agitation for 10 minutes as it is. Water was
added to the solution, which was rendered acidic by the use of 1N
hydrochloric acid, followed by extraction with ethyl acetate. The
resultant organic phase was washed with a saturated saline solution and
dried with anhydrous magnesium sulfate, from which the solvent was
distilled off. The resulting residue was dissolved in 30 ml of
dimethylformamide without purification, to which 1.94 g of 60% sodium
hydride was added at room temperature. After 10 minutes, it was cooled
down to 0.degree. C., to which 5.96 g of chloromethyl methyl ether was
added, followed by agitation for 15 minutes as it is. Water was added to
the solution which was extracted with ethyl acetate, and th resultant
organic phase was washed with a saturated saline solution and dried with
anhydrous magnesium sulfate, from which the solvent was distilled off. The
resultant residue was purified by silica gel column chromatography (3%
ethyl acetate/hexane) to obtain 8.13 g of the captioned compound as a
light yellow oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.36(d,J=6.7 Hz,6H), 3.54(s,3H),
4.29-4.65(m,1H), 5.32(s,2H), 7.00-7.84(m,6H)
Reference 12
5-Isopropyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR63##
8-Isopropyl-1-methoxymethoxynaphthalene was treated in the same manner as
in Reference 3, thereby obtaining the captioned compound as a light yellow
oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.34(d,J=6.7 Hz,6H), 3.53(s,3H),
3.98(s,3H), 4.43-4.77(m,1H), 5.26(s,2H), 7.30-7.57(m,2H), 7.76(s,1H),
8.93(dd,J=2.0 Hz,6.9 Hz,1H), 10.45(s,1H)
Reference 13
3-Methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR64##
4-Hydroxy-1-naphthalenecarbaldehyde was treated in the same manner as in
References 8, 9, thereby obtaining the captioned compound as light yellow
crystals.
Melting point: 68.degree.-68.5.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 3.59(s,3H), 4.00(s,3H),
5.40(s,2H), 7.37-7.60(m,2H), 7.76(s,1H), 8.10-8.32(m,1H), 8.86-9.10(m,1H),
10.33(s,1H)
Reference 14
4-Methoxymethoxy-3-methyl-1-naphthalenecarbaldehyde
##STR65##
4-Hydroxy-3-methyl-1-naphthalenecarbaldehyde was treated in the same manner
as in Reference 3(d), thereby obtaining the captioned compound as a light
yellow oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.51(s,3H), 3.63(s,3H),
5.16(s,2H), 7.40-7.64(m,2H), 7.74(s,1H), 7.96-8.16(m,1H), 9.04-9.24(m,1H).
10.16(s,1H)
Reference 15
3-Chloro-5-ethyl-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR66##
(a) Preparation of 5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde
##STR67##
24.0 g of 8-ethyl-1-naphthol was dissolved in 200 ml of dichloromethane, in
which 30.6 ml of titanium tetrachloride was gradually dropped under
ice-cooling conditions. Thereafter, 20.3 ml of dichloromethyl methyl ether
was gradually dropped under ice-cooling condition. After agitation for 10
minutes, 50 ml of water was gradually dropped under ice-cooling
conditions. The reaction solution was extracted with ethyl acetate and the
organic phase was washed with water. After drying with anhydrous magnesium
sulfate, the solvent was distilled off and the resultant crystals were
washed with a mixed solvent of chloroform and isopropyl ether (1:1) to
obtain 15.9 g of the captioned compound as yellowish brown crystals.
Melting point: 193-194.degree. C.
.sup.1 H-NMR(90 MHz, DMSO-d.sub.6).delta.: 1.26(d,J=7 Hz,3H), 3.32(q,J=7
Hz,2H), 7.04(d,J=8Hz,1H), 7.33(dd,J=1.4Hz,8Hz,1H) 7.56((t,J=8Hz,1H),
7.94(d,J=8 Hz,1H), 9.17(dd,J=4 Hz,8Hz,1H), 10.07(s,1H), 11.40(s,1H)
(b) Preparation of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde
##STR68##
0.81 g of 5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde and 0.49 ml of
sulfuryl chloride were heated in 30 ml of benzene under reflux for 30
minutes. The reaction solution was returned to room temperature and poured
into water, followed by extraction with ethyl acetate. The resultant
organic phase was washed with a saturated saline solution and dried with
anhydrous magnesium sulfate, followed by concentration under reduced
pressure. The resultant crystals were washed with isopropyl ether to
obtain 0.8 g of the captioned compound as yellowish brown crystals.
Melting point: 139.degree.-142.degree. C.
.sup.1 H-NMR(90 MHz, DMSO-d.sub.6).delta.: 1.28(t,J=7 Hz,3H),
3.36(q,J=7Hz,2H), 7.40(dd,J=1.8 Hz,7 Hz,1H) 7.60((t,J=7 Hz,1H), 8.12(s,1H)
9.11(dd,J=1.8 Hz,7 Hz, 1H), 10.12(s,1H)
(c) Preparation of
3-chloro-5-ethyl-4-methoxymethoxy-1-naphthalenecarbaldehyde
##STR69##
1.0 g of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde, 0.91 ml of
chloromethyl methyl ether and 3.5 ml of N,N-diisopropylethylamine were
dissolved in 10 ml of dichloromethane, and reacted at room temperature for
4 hours. The reaction solution was concentrated under reduced pressure and
the resultant residue was purified by silica gel column chromatography (5%
ethyl acetate/hexane) to obtain 0.74 g of the captioned compound as a
brown oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.27(t,J=7 Hz,3H), 3.34(q,J=7
Hz,2H), 3.60(s,3H) 5.24(s,2H), 7.20-7.64(m,2H), 7.88(s,1H), 9.02(dd,J=1.8
Hz,10.8 Hz,1H), 10.20(s,1H)
Reference 16
4-Acetoxy-3-isopropyl-5-methyl-1-naphthalenecarbaldehyde
##STR70##
(a) Preparation of 1'-hydroxy-8'-methyl-2'-acetonaphthone
##STR71##
13 g of 8-methyl-1-naphthyl acetate and 13.8 g of aluminum chloride were
reacted at 140.degree. C. for 4 hours. Water, concentrated hydrochloric
acid and ethyl acetate were added to the reaction mixture to dissolve all
solid matters, followed by extraction with ethyl acetate. The organic
phase was washed with a saturated saline solution, dried with anhydrous
magnesium sulfate and concentrated under reduced pressure. The resultant
residue was purified by silica gel column chromatography (7% ethyl
acetate/hexane) to obtain 5.5 g of the captioned compound as a yellow oily
substance.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 2.51(s,3H), 2.63(s,3H),
7.04-7.72(m,5H), 8.20(s, 1H)
(b) Preparation of 1'-benzyloxy-8'-methyl-2'-acetonaphthone
##STR72##
5.5 g of 1'-hydroxy-8'-methyl-2'-acetonaphthone was dissolved in 50 ml of
N,N-dimethylformamide, to which 1.7 g of 60% sodium hydride was added,
followed by agitation at 50.degree. C. for 10 minutes. The reaction
solution was returned to room temperature, in which 5.5 ml of benzyl
chloride was dropped, followed by heating again to 70.degree. C. for
reaction for 1hour. After returning to room temperature, water was added
to the solution, which was extracted with ethyl acetate. The resultant
organic phase was washed with a saturated saline solution, dried with
anhydrous magnesium sulfate and concentrated under reduced pressure. The
resultant reside was purified by silica gel column chromatography (15%
ethyl acetate/hexane) to obtain 4.8 g of the captioned compound as a brown
oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.52(s,3H), 2.68(s,3H),
5.08(s,2H), 7.04-8.04(m, 10H)
(c) Preparation of 1-(1-benzyloxy-8-methyl-2-naphthyl)-1-methyl-1-ethanol
##STR73##
4.8 g of 1'-benzyloxy-8'-methyl-2'-acetonaphthone was dissolved in 200 ml
of tetrahydrofuran and cooled down to -78.degree. C. At the temperature,
28 ml of a tetrahydrofuran solution of 1M methylmagnesium bromide was
added, followed by returning to room temperature. It was agitated at room
temperature for 72 hours and was further reacted at 80.degree. C. for 2
hours. The reaction solution was cooled down to 0.degree. C., to which a
saturated ammonium chloride aqueous solution was added portion by portion,
followed by extraction with ethyl acetate. The resultant organic phase was
washed with a saturated saline solution, dried with anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (10% ethyl acetate/hexane) to obtained
1.8 g of the captioned compound as a brown oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.61(s,3H), 1.68(s,3H),
2.48(s,3H), 5.12(s,2H), 6.74-8.14(m,10H)
(d) Preparation of 1-benzyloxy-2-isopropenyl-8 methylnaphthalene
##STR74##
1.8 g of 1-(1-benzyloxy-8-methyl-2-naphthyl)-1-methyl-1-ethanol was
dissolved in 20 ml of tetrahydrofuran, to which 30 ml of 3N hydrochloric
acid was added, followed by refluxing for 2 hours. The reaction solution
was returned to room temperature, to which water was added, followed by
extraction with ethyl acetate. The resultant organic phase was washed with
a saturated saline solution, dried with anhydrous magnesium sulfate and
concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (4% ethyl acetate/hexane) to obtain 1.0 g of the
captioned compound as a yellowish green oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 2.25(s,3H). 2.49(s,3H),
4.97(s,2H), 5.17-5.33(m,2H), 6.95-7.97(m,10H)
(e) Preparation of 2-isopropyl-8-methyl-1-naphthol
##STR75##
1.0 g of 1-benzyloxy-2-isopropenyl-8-methylnaphthalene and 0.1 g of 10%
palladium-carbon (water content of 50%) were added to 40 ml of ethanol and
hydrogenated at normal temperatures and normal pressures. The
palladium-carbon was filtered through Celite, after which the filtrate was
concentrated under reduced pressure to obtain 0.65 g of the captioned
compound as a black oily substance.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.32(d,J=7 Hz,6H), 2.51(s,3H),
3.31(m,1H), 5.24(br, s,1H), 7.03-8.25(m,5H)
(f) Preparation of 3-isopropyl-4-hydroxy-5-methyl-1-naphthalenecarbaldehyde
##STR76##
0.65 g of 2-isopropyl-8-methyl-1-naphthol was dissolved in 50 ml of
dichloromethane and cooled down to 0.degree. C. 1.3 ml of titanium
tetrachloride was gradually dropped in the solution for reaction at
0.degree. C. for 5 minutes, after which 0.9 ml of dichloromethyl methyl
ether was gradually dropped and reacted at 0.degree. C. for 1 hour. Water
was added to the reaction solution, which was extracted with ethyl
acetate. The resultant organic phase was washed with a saturated saline
solution, dried with anhydrous magnesium sulfate and concentrated under
reduced pressure. The resulting crystals were collected by filtration to
obtain 0.7 g of the captioned compound as black crystals.
Melting point: 125.degree.-128.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.38(d,J=7 Hz,6H), 2.55(s,3H),
3.36(m,1H), 7.03-7.71(m, 2H), 7.71-8.03(m,2H), 9.16(m,1H), 10.38(s,1H)
(g) Preparation of 4-acetoxy-3-isopropyl-5-methyl-1-naphthalenecarbaldehyde
##STR77##
0.7 g of 3-isopropyl-4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 10 ml
of acetic anhydride were dissolved in 10 ml of pyridine and reacted at
room temperature for 1 hour. The reaction solution was poured into water
and extracted with ethyl acetate. The organic phase was washed with dilute
hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution
and a saturated saline solution in this order, dried with anhydrous
magnesium sulfate and concentrated under reduced pressure, thereby
obtaining 0.5 g of the captioned compound as a black oily substances.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.32(d,J=7 Hz,6H), 2.52(s,6H),
3.18(m,1H), 6.80-7.52(m, 2H), 7.84(s, 1H), 9.02(m,1H), 10.26(s,1H).
Reference Example 17
5-ethyl-4-methoxymethoxy-3-pentyloxy-1-naphthalene carbaldehyde
##STR78##
The above-captioned compound can be obtained as a yellow-brown oily product
in the same procedures as those in Reference Examples 3(c) and (d) by
using pentyl bromide instead of methyl iodide in Reference Example 3(b).
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 0.80.about.1.10 (m, 3H),
1.14.about.1.62(m,7H), 1.68.about.2.04 (m, 2H), 3.38 (q, J=7 Hz,2H), 3.54
(s, 3H), 4.14 (t, J=7Hz, 2H), 5.32 (s, 2H), 7.18.about.7.50(m, 2H),
7.74(s, 1H), 8.90(dd, J=2.6 Hz, 7 Hz, 1H), 10.44(s, 1H)
Reference Example 18
5-ethyl-3methoxyethoxy-4-methoxymethoxy-1naphthalene carbaldehyde
##STR79##
The above-captioned compound can be obtained as a yellow-brown oily product
in the same procedures as those in Reference Examples 3 (c) and (d) by
using 2-bromoethyl methyl ether instead of methyl iodide in Reference
Example (b).
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.30 (t, J=3Hz, 3H), 3.38 (q,
J=7Hz, 2H), 3.42 (s, 3H), 3.52 (s, 3H), 3.68.about.3.86 (m, 2H),
4.16.about.4.34 (m, 2H), 5.36 (s, 2H), 7.20.about.7.52 (m, 2H), 7.76 (s,
1H), 8.92 (dd, J=2.6 Hz, 7 Hz, 1H), 10.32 (s, 1H)
Reference Example 19
1-(t-butyldimethylsilyl)oxymethyl-5-ethyl-4-methoxymethoxy naphthalene
##STR80##
The above-captioned compound can be obtained as a yellow oily product by
treating 8-ethyl-1-naphthol in the same procedures as those in Reference
Example 6.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 0.12 (s, 6H), 0.94 (s, 9H),
1.32(t,J=7 Hz, 3H), 3.30 (q, J=7 Hz, 2H), 3.52 (s, 3H), 5.04 (s, 2H), 5.28
(s, 2H), 7. 00 (d, J=7 Hz, 1H), 7.10.about.7.40 (m, 3H), 7.72 (dd, J=2.6
Hz, 7 Hz)
Reference Example 20
3-benzyloxy-5-ethyl-4-methoxymethoxy-1-naphthalene carbaldehyde
##STR81##
The above-captioned compound was obtained as a yellow oily product by
processing 1-(t-butyldimethylsilyl)oxymethyl-5-ethyl-4-methoxymethoxy
naphthalene obtained in Reference Example 19 by using benzyl bromide
instead of methyl iodide.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.30 (t. J=7 Hz, 3H), 3.38 (q,
J=7 Hz, 2H), 3.46 (s, 3H), 5.20 (s, 2H), 5.32 (s, 2H), 7.18.about.7.54 (m,
7H), 7.80 (s, 1H), 8.92 (dd, J=2.6 Hz, 7 Hz, 1H), 10.28 (s, 1H)
Reference Example 21
1-methoxymethoxy-8-(3-methoxypropyl)naphthalene
(a) Synthesis of 8-methoxymethoxy-1-naphthalene carbaldehyde
##STR82##
9.5 g of 8-hydroxy-1-naphthol was dissolved in 210 ml of acetone, to which
22.7 g of hydrous potassium carbonate and 5.43 ml of chloromethyl methyl
ether were added and refluxed for one hour under heating. The reaction
solution was filtered and the filtrate was concentrated. 12.2 g of thus
obtained yellow oily product was dissolved with no further purification
into 250 ml of dichloromethane, to which 4.3 g of pyridinium trifluoro
acetate and 18.3 g of pyridinium dichromate were added and stirred at a
room temperature for 12 hours. After filtering off insoluble matters, the
filtrate was concentrated and then purified on silica gel column
chromatography (10% ethyl acetate-mexane), to obtain in 5.1 g of the
above-captioned compound as colorness crystals.
m.p.; 56.degree..about.57.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 3.50 (s, 3H), 5.35 (s, 2H),
7.16.about.8.00 (m, 6H), 11.11 (s, 1H)
(b) Synthesis of ethyl 3-(8-methoxymethoxy-1-naphthyl) propenoate
##STR83##
A liquid suspension of 1.36 g of 60% sodium hydride in 50 ml of
1,2-dimethoxyethane was incorporated with 7.63 g of triethylphosphono
acetate under ice cooling and stirred For 5 min. A solution of 4.9 g of
8-methoxymethoxy-1-naphthalene carbaldehyde in 30 ml of 1,2-dimethoxy
ethane was dropped to the resultant clear solution and stirred for 10 min.
After the reaction was over, water was added and extracted with ethyl
acetate, the organic layer was washed with a saturated aqueous solution of
sodium chloride and then dried over anhydrous magnesium sulfate. When the
residue obtained by distilling off the solvent was purified on silica gel
column chromatography (10% ethyl acetate-hexane), 6.4 g of the
above-captioned compound was obtained as pale brown oily product.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.36 (t, J=7 Hz, 3H), 3.54 (s,
3H), 4.28 (q, J=7 Hz, 2H), 5.32 (s, 2H), 6.14 (d, J=15 Hz, 1H),
7.08.about.7.87 (m, 6H), 8.93 (d, J=15 Hz, 1H)
(c) Synthesis of 8-(3-hydroxypropyl)-2-methoxymethoxy naphthalene
##STR84##
6.4 g of ethyl 2-(8-methoxymethoxy)propenoate was dissolved in 60 ml of
tetrahydrofuran, to which 0.6 g of 10% palladium carbon (50% hydrous
product) and hydrogenated at normal temperature and normal pressure for 4
hours. After the reaction was over, palladium carbon was removed by
filtration and the filtrate was concentrated. The resultant colorless oily
product was dissolved in 20 liter of tetrahydrofuran and dropped under ice
cooling to 0.62 g of aluminum lithium hydride previously suspended in 20
ml of tetrahydrofuran. After stirring at a room temperature for one hour
after dropping, it was cooled again with ice and water and 1N-hydrochloric
acid was added. The reaction solution was extracted with ethyl acetate,
washed with saturated aqueous solution of sodium chloride and then dried
over anhydrous magnesium sulfate. When the residue obtained by distilling
off the solvent was purified on silica gel column chromatography (30%
ethyl acetate-hexane), 5.2 g of the above-captioned compound was obtained
as a colorless oily product.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.51 (br. s, 1H), 1.82.about.2.15
(m, 2H), 3.37 (m, 2H), 3.56 (s, 3H), 3.72 (t, J=7 Hz, 2H), 5.34 (s, 2H),
7.03.about.7.72 (m, 6H)
(d) 2-methoxymethoxy-8-(3-methoxypropyl) naphthalene
##STR85##
5.1 g of 8-(3-hydroxypropyl)-1-methoxymethoxy naphthalene was dissolved in
40 ml of N,N-dimethyl formamide, to which 1.4 g of 55% sodium hydride was
added under ice cooling. Then, 1.93 ml of methyl iodide was added and
stirred at a room temperature for 2 hours. After adding water to the
reaction solution and extracting with ethyl acetate, the organic layer was
washed with water and then with a saturated aqueous solution of sodium
chloride successively and then dried over magnesium sulfate. After
distilling off the solvent, when it was purified on silica gel column
chromatography (10% ethyl acetate-hexane), 5.3 g of the above-captioned
compound was obtained as a colorless oily product.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.89.about.2.13 (m, 2H),
3.22.about.3.54 (m, 4H), 3.35 (s, 3H), 3.54 (s, 3H), 5.34 (s, 2H).
7.04.about.7.72 (m, 6H).
Reference Example 22
3-methoxy-4-methoxymethoxy-5-(3-methoxypropyl) naphthalene carbaldehyde
##STR86##
The above-captioned compound was obtained as a pale yellow oily product
from 1-methoxymethoxy-8-(3-methoxypropyl)naphthalene by the same
procedures as those in Reference Example 3.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.85.about.2.11 (m, 2H),
3.28.about.3.57 (m, 4H), 3.34(s, 3H), 3.55 (s, 3H), 4.02 (s,3H), 5.34 (s,
2H), 7.30.about.7.54 (m, 2H), 7.82 (s, 1H), 8.98 (dd,J=2.6 Hz, 7 Hz, 1H),
10.44 (s, 1H)
Reference Example 23
5-ethyl-1-methoxymethoxy naphthalene
(a) Synthesis of 5-bromo-1-methoxymethoxy naphthalene
##STR87##
6.0 g of 5-bromo-1-naphthol was dissolved in 50 ml of
N,N-dimethylformamide, to which 1.2 g of 60% sodium hydride was added.
After stirring at a room temperature for 10 min, it was cooled to
0.degree. C., to which 3.5 ml of chloromethyl methyl ether was added and
stirred for 10 min. Water was added to the reaction solution, which was
extracted with ethyl acetate. The extract was washed with a saturated
aqueous solution of sodium chloride, dried over anhydrous magnesium
sulfate and then the solvent was distilled When the resultant residue was
purified on silica gel column chromatography (10% ethyl acetate/hexane),
7.2 g of the above-captioned compound was obtained as red articular
crystals.
m.p.: 49.degree.-50.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 3.51 (s, 3H), 5.34 (s, 2H), 7.09
(br. d, J=7 Hz; 1H), 7.20.about.7.36 (m, 1H), 7.42 (t, J=7 Hz, 1H), 7.73
(br. d, J=7 Hz, 1H), 7.78 (t, J=7 Hz, 1H), 8.21 (br. d, J=7 Hz, 1H)
(b) Synthesis of 5-ethyl-1-methoxymethoxy naphthalene
##STR88##
6.9 g of 5-bromo-1-methoxymethoxy naphthalene was dissolved in 100 ml of
anhydrous tetrahydrofuran and cooled to -60.degree. C. 21.3 ml of a hexane
solution containing 1.6M of n-butyl lithium was gradually added to the
solution. After stirring at -40.degree. C.--60.degree. C. for one hour,
the reaction solution was cooled to -65.degree. C. and 4.2 ml of ethyl
iodide was slowly dropped. After the dropping, the temperature was warmed
up to the room temperature, water was added and the solution was extracted
with ethyl acetate. After washing the extract with an aqueous saturated
solution of sodium chloride and drying over anhydrous magnesium sulfate,
the solvent was distilled off. When the residue was purified on silica gel
column chromatography (7% ethyl acetate/hexane), 5.5 g of the
above-captioned compound was obtained as a pale yellow oily product.
.sup.1 H-NMR (90 MHz. CDCl.sub.3).delta.: 1.35 (t. J=7 Hz, 3H), 3.06 (q.
J=7 Hz, 2H), 3.51 (s, 3H), 5.33 (s, 2H), 6.92.about.7.08 (m, 1H),
7.11.about.7.47 (m, 3H), 7.51.about.7.61 (m, 1H), 7.92.about.8.40 (m, 1H)
Reference Example 24
7-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalene carbaldehyde
##STR89##
When 5-ethyl-1-methoxymethoxy naphthalene was treated in the same
procedures as those in Reference Example 3, the above-captioned compound
was obtained as a colorless oily product.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.38 (t, J=7 Hz, 3H), 3.08 (q,
J=7 Hz, 2H), 3.58 (s, 3H), 3.93 (s, 3H), 5.36 (s, 2H), 7.30.about.7.58 (m,
2H), 7.82 (s, 1H), 8.17 (dd, J=3.6 Hz, 7 Hz, 1H), 10.75 (s, 1H)
Reference Example 25
7-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalene carbaldehyde
##STR90##
(a) Synthesis of 6-ethyl-2-methoxy-naphthol
##STR91##
4.4 g of 6-ethyl-3-methoxy-1-naphthalene carbaldehyde and 4.9 g of 80-85%
m-chloroperbenzoic acid were dissolved in 40 ml of dichloromethane and
then refluxed under heating for 30 min. The solution was cooled to
0.degree. C. and after adding an aqueous saturated solution of sodium
thiosulfate and stirring for 20 min, insoluble matters were removed by
filtration and then the filtrate was extracted with ethyl acetate. The
extract was washed with a saturated aqueous solution of sodium chloride
and then dried over anhydrous magnesium sulfate.
7.0 g of a brown oily product obtained by distilling off the solvent was
dissolved into 20 ml of methanol with no further purification. Then, an
aqueous solution of potassium hydroxide (potassium hydroxide 2.0 g/water
10 ml) was added and refluxed under heating for 30 min. The reaction
solution was cooled to 0.degree. C., rendered acidic with addition of
diluted hydrochloric acid, and extracted with ethyl acetate. After washing
the extract with an aqueous saturated solution of sodium chloride, it was
dried over anhydrous magnesium sulfate. When the residue obtained by
distilling off the solvent was purified on silica gel column
chromatography (10% ethyl acetate/hexane), 3.3 g of the above-captioned
compound was obtained as pale brown plate-like crystals.
m.p.: 68.degree.-69.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.31 (t, J=7Hz, 3H), 2.77 (q,
J=7Hz, 2H), 3.96 (s, 3H), 6.97 (br. s, 1H), 7.08.about.740 (m, 3H), 7.49
(hr. s, 1H), 8.06 (d, J=7 Hz, 1H)
(b) 7-ethyl-hydroxy-3-methoxy-1-naphthalene carbaldehyde
##STR92##
3.3 g of 6-ethyl-2-methoxy-1-naphthol was dissolved in 25 ml of
dichloromethane and cooled to 0.degree. C. 3.65 ml of titanium
tetrachloride and 2.4 ml of dichloromethyl methyl ether were added
successively at that temperature and stirred for 10 min. After the
reaction was over, water was added and the solution was extracted with
ethyl acetate. After washing the extract with an aqueous saturated
solution of sodium chloride, it was dried over anhydrous magnesium
sulfate. When the solvent was distilled off and deposited crystals were
washed with isopropyl ether, 2.5 g of the above-captioned compound was
obtained as brown crystals.
m.p.: 114.degree.-116.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.34 (t, J=7 Hz, 3H), 2.83 (q,
J=7 Hz, 2H), 3.04 (s, 3H), 6.59 (s, 1H), 7.36 (dd, J=3 Hz, 9 Hz, 1H), 7.79
(s, 1H), 8.11 (d, J=9 Hz, 1H), 8.83 (m, 1M), 10.35 (s, 1H)
(c) Synthesis of 7-ethyl-3-methoxy-4-methoxymethoxy 1-naphthalene
carbaldehyde
##STR93##
2.5 g of 7-ethyl-4-hydroxy-3-methoxy-1-naphtalane carbaldehyde was
dissolved in 20 ml of N,N-dimethylformamide, to which 0.52 g of 60% sodium
hydride was added and stirred for 10 min. The reaction solution was cooled
to 0.degree. C., to which 1.3 ml of chloromethyl methyl ether was slowly
dropped. After stirring for 10 min at a room temperature, water was added
and the solution was extracted with ethyl acetate. After washing the
extract with a saturated aqueous solution of sodium chloride, it was dried
over anhydrous magnesium sulfate. When the residue obtained by distilling
off the solvent on silica gel chromatography (10% ethyl acetate/hexane),
2.8 g of the above-captioned compound was obtained as a yellow oily
product.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.: 1.32 (t, J=7 Hz, 3H), 2.82 (q,
J=7 Hz, 2H), 3.57 (s, 3H), 3.96 (s, 3H), 5.38 (s, 2H), 7.38 (dd, J=3 Hz, 9
Hz, 1H), 7.71 (s, 1H), 8.15 (d, J=9 Hz, 1H), 8.82 (m, 1H), 10.37 (s, 1H)
Example 1
(E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR94##
(a) Preparation of ethyl
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate
##STR95##
36 g of 60% sodium hydride was suspended in 500 ml of
N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was
added at ice bath temperature. After stirring at room temperature for 1
hour, a solution of 206 g of
5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added.
After stirring at room temperature for 15 minutes, ice cooled water was
gradually added at ice bath temperature. The mixture was extracted with
ethyl acetate and the combined organic layer was washed with brine. After
drying over anhydrous magnesium sulfate, the solvent was evaporated and
the residue was purified by silica gel column chromatography (10% ethyl
acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil
(containing a small amount of Z isomer).
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.30(t,J=7 Hz,3H), 1.38(t,J=7
Hz,3H), 1.96(d,J=1.3 Hz,3H), 3.34(q,J=7 Hz,2H), 3.57(s,3H), 3.91(s,3H),
4.28(q,J=7 Hz,2H), 5.17(s,2H), 7.04-7.31(m,3H), 7.60(m,1H), 8.03(br.s,1H).
(b) (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic
acid
##STR96##
28 g of ethyl
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate
was dissolved in 240 ml of ethanol and a potassium hydroxide aqueous
solution (potassium hydroxide 28 g/water 55 ml) was added, followed by
refluxing for 1 hour. 280 ml of 2N hydrochloric acid was added to the
reaction mixture at ice bath temperature to make it acidic, followed by
extraction with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate, and evaporated. Diisopropyl ether
was added to the resultant residue and the resultant crystals were
filtered to obtain 23 g of the titled compound as pale yellow crystals.
Melting point: 127.degree.-128.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.28(t,J=7 Hz,3H), 2.00(d,J=1.8
Hz,3H), 3.35(q,J=7Hz,2H), 3.56(s,3H), 3.93(s,3H), 5.19(s,2H),
7.17-7.29(m,3H), 7.61-7.71(m,1H), 8.26(s,1H),
(c) (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR97##
23 g of
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic
acid was dissolved in 230 ml of acetone and 15 ml of concentrated
hydrochloric acid was added slowly at room temperature. After stirring at
room temperature for 1.5 hours, the reaction mixture was gradually poured
into 3.5 liters of water. The resultant crystals were filtered, washed
with water and dried to obtain 19 g of the titled compound as pale yellow
crystals.
Melting point: 194.degree.-195.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.33(t,J=7 Hz,3H), 2.04(d,J=1.3
Hz,3H), 3.34(q,J=7 Hz,2H), 3.97(s,3H), 6.47(s,1H), 7.12-7.35(m,3H),
7.52-7.75(m,1H), 8.27(s,1H).
Example 2
(Z)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR98##
(a) Ethyl
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate
##STR99##
5.6 g of ethyl
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate
was dissolved in 300 ml of acetone and irradiated for 2 hours with light
from a high pressure mercury lamp through a Pyrex filter. The solvent was
evaporated and the resultant residue was purified by silica gel column
chromatography (3% ethyl acetate/hexane) to obtain 6.6 g of the titled
compound as a yellow oil. At the same time, 9.0 g of a mixture of E and Z
isomers was obtained.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.75(t,J=7 Hz,3H), 1.28 (t,J=7
Hz,3H), 2.19(d,J=1.8 Hz,3H), 3.34(q,J=7 Hz,2H), 3.57 (s,3H), 3.83(q,J=7
Hz,2H), 3.89(s,3H), 5.13(s,2H), 7.01-7.31(m,4H), 7.53-7.74(m,1H).
(b) Preparation of
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-napthyl)-2-methylpropenoic
acid
##STR100##
71.2 g of ethyl
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate
was dissolved in 600 ml of ethanol and a potassium hydroxide aqueous
solution (potassium hydroxide 71 g/water 140 ml) was added, followed by
refluxing for 1 hour. The reaction mixture was cooled on an ice bath,
after which 700 ml of 2N hydrochloric acid was added to make it acidic,
followed by extraction with ethyl acetate. The organic layer was washed
with brine, dried over anhydrous magnesium sulfate. The solvent was
evaporated to obtain 66 g of the titled compound as a yellow oil.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.24(t,J=7 Hz,3H), 2.16(d,J=1.8
Hz,3H), 3.32(q,J=7 Hz,2H), 3.52(s,3H), 3.81(s,3H), 5.15(s,2H),
7.08-7.32(m,4H), 7.44-7.68(m,1H).
(c) Preparation of
(Z)-3-(5-ethyl-4-hydroxy3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR101##
66 g of
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-naphthyl)-2-methyl
propenoic acid was dissolved in 700 ml of acetone in which nitrogen had
been preliminarily bubbled, and 43 ml of concentrated hydrochloric acid
was gradually added while stirring at room temperature in a stream of
nitrogen under light-shielded conditions. After stirring at room
temperature for 1.5 hours, the reaction mixture was gradually poured into
water to crystalize. The crystals were filtered, washed with water and
dried to obtain 50.0 g of the titled compound as yellow crystals.
Melting point: 190.degree.-191.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.31(t,J=7 Hz,3H), 2.16(d,J=1.5
Hz,3H), 3.31(q,J=7 Hz,2H), 3.76(s,3H), 6.34(br.s,1H), 7.04-7.32(m,4H),
7.42-764 (m,1H).
Examples 3-8
The 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde and
suitable Witting reagents were reacted, followed by treatment in the same
manner as in Examples 1 and 2 to obtain compounds of Examples 3 to 8
indicated in Table 2.
TABLE 2
______________________________________
No. NMR data (90 MHz)
______________________________________
3 1.32(t, J=7Hz, 3H), 3.34(q, J=7Hz, 2H),
4.02(s, 3H), 6.36(d, J=15Hz, 1H),
6.86(br.s, 1H), 7.08.about.7.36(m, 2H),
7.50(s, 1H), 7.92(dd, J=2.6Hz, 7.7Hz, 1H),
8.46(d, J=15Hz, 1H)
(CDCl.sub.3 -DMSO-d.sub.6)
4 1.06(t, J=7Hz, 3H), 1.15(t, J=7Hz, 3H),
2.16.about.2.50(m, 2H), 3.10.about.3.45(m, 2H),
3.90(s, 3H), 7.08.about.7.64(m, 4H), 7.91(s, 1H),
9.12(s, 1H), 12.51(br.s, 1H)
(DMSO-d.sub.6)
5 1.16(t, J=7Hz, 3H), 1.25(t, J=7Hz, 3H),
2.28.about.2.60(m, 2H), 3.08.about.3.48(m, 2H),
3.83(s, 3H), 7.01(m, 1H), 7.04.about.7.32(m, 2H),
7.63(m, 1H), 8.89(s, 1H), 12.35(m, 1H)
(DMSO-d.sub.6)
6 1.22(t, J=7Hz, 3H), 3.13.about.3.40(m, 2H),
3.31(s, 3H), 6.74(s, 1H), 7.04.about.7.39(m, 7H),
7.83(m, 1H), 8.32(s, 1H), 9.18(s, 1H),
12.69(m, 1H)
(DMSO-d.sub.6)
7 1.30(t, J=7Hz, 3H), 3.32(q, J=7Hz, 2H),
3.50(s, 3H), 3.86(s, 2H), 6.40(br.s, 1H),
7.00.about.7.40(m, 8H),
7.68(dd, J=2.6Hz, 7.7Hz, 1H), 8.50(s, 1H)
(CDCl.sub.3)
8 1.30(t, J=7Hz, 3H), 3.30(q, J=7Hz, 2H),
3.72(s, 3H), 3.80(s, 2H), 6.36(br.s, 1H),
7.0.about. 7.58(m, 10H)
(CDCl.sub.3)
______________________________________
Ex- Intended Compounds
am- Appearance Melting
ple Structural Formula.
NMR Spectrum
Point
No. Name of Compound (90 MHz) (.degree.C.)
______________________________________
3 (E)-3-(5-ethyl-4-hydroxy-
yellow over 185
3-methoxy-l-naphthyl)-
crystals (decom-
propenoic acid posed)
4 (E)-2-ethyl-3-(5-ethyl-4-
pale 171-173
hydroxy-3-methoxy-l-naphthyl)-
yellow
propenoic acid crystals
5 (Z)-2-ethyl-3-(5-ethyl-4-
yellow 134-136
hydroxy-3-methoxy-l-naphthyl)-
crystals
propenoic acid
6 (E)-3-(5-ethyl-4- yellow 180-181
hydroxy-3-methoxy-l-naphthyl)-
crystals
2-phenylpropenoic acid
7 (E)-2-benzyl-3-(5-ethyl-4-
pale 174-176
hydroxy-3-methoxy-l-naphthyl)-
yellow
propenoic acid crystals
8 (Z)-2-benzyl-3-(5-ethyl-4-
yellow 129-131
hydroxy-3-methoxy-l-naphthyl)-
crystals
propenoic acid
______________________________________
(formulae of the example compounds)
##STR102##
4
##STR103##
5
##STR104##
6
##STR105##
7
##STR106##
8
##STR107##
______________________________________
Example 9
(Z)-3-(4-acetoxy-5-ethyl-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR108##
(a) Preparation of
(E)-3-(4-acetoxy-5-ethyl-3-methoxy-1-naphthyl-2-methylpropenoic acid
##STR109##
440 mg of (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic
acid was dissolved in 2.4 ml of pyridine and 0.42 ml of acetic anhydride
was added, followed by stirring at room temperature for 1 hour. The
reaction mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed with dilute hydrochloric acid and water in
this order, dried over anhydrous magnesium sulfate and concentrated in
vacuo. The resultant crystals were washed with hexane to obtain 390 mg of
the titled compound as colorless crystals.
Melting point: 195.degree.-196.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.34(t,J=7 Hz,3H), 2.01(d,J=1.5
Hz,3H), 2.41(s,3H), 3.12(q,J=7 Hz,2H), 3.91(s,3H), 7.14-7.36(m,3H),
7.56-7.73 (m,1H), 8.22(m,1H).
(b) Preparation of
(Z)-3-(4-acetoxy-5-ethyl-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR110##
1.15 g of (E)-3-(4-acetoxy-5-ethyl-3-methoxy-1-naphthyl)-2-methylpropenoic
acid was dissolved in 200 ml of acetone and irradiated with light from a
high pressure mercury lamp through a Pyrex filter at room temperature for
3 hours. The reaction mixture was concentrated in vacuo and purified by
silica gel column chromatography (3% methanol/chloroform) to obtain 470 mg
of the titled compound as colorless crystals.
Melting point: 148.degree.-150.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.31(t,J=7 Hz,3H), 2.16(d,J=1.5
Hz,3H), 2.39(s,3H), 3.08(q,J=7 Hz,2H), 3.80(s,3H), 7.08-7.32(m,4H),
7.50-7.69 (m,1H), 8.60(br.s,1H).
Example 10
(E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR111##
(a) Preparation of ethyl
(E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate
##STR112##
45 g of 60% sodium hydride was suspended in 650 ml of N,N-dimethylformamide
and cooled to 10.degree. C. 355 g of triethyl 2-phosphonopropionate was
added to the solution to make a clear solution. A solution of 270 g of
3-methoxy-4-methoxymethoxy-5-propyl-1-naphthalenecarbaldehyde in
N,N-dimethylformamide (250 ml) was dropped in the solution and stirred at
room temperature for 1 hour. The reaction mixture was poured into brine
and extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate and concentrated in vacuo. The
residue was purified by silica gel column chromatography (8% ethyl
acetate/hexane) to obtain 325.3 g of the titled compound as a pale yellow
oil (containing a small amount of Z isomer).
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.98(t,J=7 Hz,3H), 1.38(t,J=7
Hz,3H), 1.44-1.92(m,2H), 1.96(d,J=1.8 Hz,3H), 3.12-3.38(m,2H), 3.58(s,3H),
3.92(s,3H), 4.29(q,J=7 Hz,2H), 5.16(s,2H), 7.04-7.32(m,2H), 7.24(s,1H),
7.48-7.72(m,1H), 8.04(br.s,1H).
(b) Preparation of
(E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic
acid
##STR113##
2.2 g of ethyl
(E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate
was dissolved in 50 ml of ethanol. A sodium hydroxide aqueous solution
(sodium hydroxide 1.4 g/water 50 ml) was added, followed by stirring at
60.degree. C. for 30 minutes. After cooling to room temperature, dilute
hydrochloric acid was added to make the reaction mixture acidic, and
extracted with ethyl acetate. The organic layer was washed with brine,
dried over anhydrous magnesium sulfate and concentrated in vacuo. The
resultant crystals were filtered to obtain 1.9 g of the titled compound as
pale yellow crystals.
Melting point: 128.degree.-129.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.98 (t,J=7Hz, 3H),
1.44-1.92(m,2H), 2.02(d,J=1.8 Hz, 3H), 3.08-3.40(m,2H), 3.58(s,3H),
3.94(s,2H), 5.18(s,2H), 7.04-7.36(m,3H), 7.48-7.72(m,1H), 8.00(br.s,1H),
8.22(br.s,1H).
(c) Preparation of
(E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl-2-methylpropenoic acid
##STR114##
1.9 g of
(E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic
acid was dissolved in 80 ml of acetone and 40 ml of water and 3 ml of
concentrated hydrochloric acid was added, followed by stirring at
50.degree. C. for 2 hours. After cooling to room temperature the reaction
mixture was poured into water, and the resultant crystals were filtered
and washed with hexane. 1.5 g of the titled compound was obtained as pale
yellow crystals.
Melting point: 170.degree.-172.degree. C.
.sup.1 H-NMR(90 MHz, DMSO-d.sub.6).delta.: 0.94(t,J=7 Hz,3H), 1.66(m,2H),
1.94(br.s,3H), 2.98-3.50 (m,2H), 3.90(s,3H), 7.02-7.78(m,4H),
8.00(br.s,1H), 9.14(br.s,1H), 12.45(br.s,1H).
Example 11
(Z)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR115##
(a) Preparation of ethyl
(Z)-3-(3-methoxy-4-methoxy-methoxy-5-propyl-1-naphthyl)-2-methylpropenoate
##STR116##
196.5 g of ethyl
(E)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate
was dissolved in 2.6 liters of acetone and irradiated with light from a
high pressure mercury lamp through a Pyrex filter for 2.5 hours. The
reaction mixture was concentrated in vacuo and purified by silica gel
column chromatography (3% ethyl acetate/hexane) to obtain 59.2 g of the
titled compound as a pale yellow oil. At the same time, 136.4 g of a
mixture of the E and Z isomers was recovered.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.74(t,J=7 Hz,3H), 0.96(t,J=7
Hz,3H), 1.42-1.90(m,2H), 2.18(d,J=1.8Hz,3H), 3.10-3.38(m,2H), 3.56(s,3H),
3.82(q,J=7 Hz,2H), 3.90(s,3H), 5.12(s,2H), 6.98-7.28 (m,3H), 7.20(s,1H),
7.50-7.72(m,1H).
(b) Preparation of
(Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic
acid
##STR117##
70 g of ethyl
(Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoate
was dissolved in 850 ml of ethanol and a potassium hydroxide aqueous
solution (potassium hydroxide 60 g/water 120 ml) was added, followed by
refluxing for 1 hour. After cooling to 10.degree. C., 2.5N hydrochloric
acid was added to make it pH.about.5, followed by extraction with ethyl
acetate. The organic layer was washed with brine, dried over anhydrous
magnesium sulfate and concentrated in vacuo. The resultant crystals were
filtered to obtain 151 g of the titled compound as yellow crystals.
Melting point: 67.degree.-68.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.96(t,J=7 Hz,3H),
1.40-1.90(m,2H), 2.16(d,J=1.8Hz,3H), 3.08-3.36(m,2H), 3.52(s,3H),
3.80(s,3H), 5.12(s,2H), 7.00-7.36(m,3H), 7.20(s,1H), 7.40-7.68(m,1H).
(c) preparation of
(Z)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR118##
2.2 g of
(Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2naphthyl)-2-methyl
propenoic acid was dissolved in 40 ml of acetone, to which 2.5 ml of
concentrated hydrochloric acid was added under light-shielding conditions,
followed by stirring in a stream of nitrogen at room temperature for 2
hours. The reaction mixture was poured into water, and the resultant
crystals were filtered, washed with hexane and dried in vacuo to obtain
1.7 g of the titled compound as yellow crystals.
Melting point: 170.degree.-172.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.98(t,J=7 Hz,3H),
1.42-1.94(m,2H), 2.18(d,J=1.8 Hz,3H), 3.08-3.34(m,2H), 3.90(s,3H),
4.68(br.s,1H), 6.98-7.30 (m,4H), 7.62(dd,J=1.8 Hz,7 Hz,1H).
Examples 12-15
The 3-methoxy-4-methoxymethoxy-5-propyl-1naphthalenecarbaldehyde obtained
in Reference 4 and suitable Witting reagents were reacted, followed by
treatment in the same manner as in Examples 10 and 11 to obtain compounds
of Examples 12 to 15 indicated in Table 3.
TABLE 3
__________________________________________________________________________
Intended Compounds
Appear-
Ex- ance Melt-
am-
Structural NMR ing
ple
Formula. Spectrum
Point
No.
Name of Compound
(90 MHz)
(.degree.C.)
chemical formula NMR data (90
__________________________________________________________________________
MHz)
12 (E)-3-(4-hydroxy-3- methoxy-5-propyl-l- naphthyl)-propenoic
yellow crystals
187- 189
##STR119## 0.94(t, J=7Hz, 3H),
1.36.about.1.88(m, 2H),
3.00.about.3.40(m, 2H),
3.95(s, 3H), 6.49(d,
J=15Hz, 1H),
6.92.about.7.36(m, 2H),
7.64.about.7.96(m, 2H),
8.26(d, J=15Hz, 1H),
9.46(br.s, 1H),
12.27(br.s,
1H) (DMSO-d.sub.6)
13 (E)-2-ethyl-3-(4-hydroxy- 3-methoxy-5-propyl-l- naphthyl)-propenoic
acid pale yellow crystals
175- 176
##STR120## 0.95(t, J=7Hz, 3H),
1.07(t, J=7Hz, 3H),
1.53.about.1.80(m, 2H),
2.20.about.2.50(m, 2H),
3.13.about.3.36(m, 2H),
3.90(s, 3H), 7.05.about.7.3
2(m, 2H), 7.53(m, 1H),
7.93(s, 1H), 9.10(s, 1H)
(DMSO-d.sub.6)
14 (Z)-2-ethyl-3-(4-hydroxy- 3-methoxy-5-propyl-l- naphthyl)-propenoic
acid pale yellow crystals
134- 136
##STR121## 0.94(t, J=7Hz, 3H),
1.16(t, J=7Hz, 3H),
1.4.about.1.9(m, 2H),
2.3.about.2.6(m, 2H),
3.1.about.3.4(m, 2H),
3.82(s, 3H), 6.98(m, 1H),
7.0.about.7.25(m, 3H),
7.60(m, 1H), 8.85(s, 1H),
12.37(br.s,
1H) (DMSO-d.sub.6)
15 (Z)-2-benzyl-3-(4- hydroxy-3-methoxy-5- propyl-1-naphthyl) propenoic
acid yellow crystals
104- 106
##STR122## 0.98(t, J=7Hz, 3H),
1.44.about.1.92(m, 2H),
3.04.about.3.32(m, 2H),
3.66(s, 3H), 3.76(s, 2H)
6.32(br.s, 1H),
7.00.about.7.36(m, 8H),
7.46(dd, J=3.6Hz, 7Hz,
1H), 7.82(br.s, 1H)
(CDCl.sub.3)
__________________________________________________________________________
Example 16
(Z)-3-(4-acetoxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR123##
(a) Preparation of
(E)-3-(4-acetoxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR124##
7.1 g of (E)-3-(4-hydroxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic
acid was dissolved in 20 ml of pyridine and 2 ml of acetic anhydride was
added, followed by stirring at room temperature overnight. The reaction
mixture was concentrated in vacuo and the resultant crystals were filtered
and washed with ethyl acetate to obtain 7.5 g of the titled compound as
colorless crystals.
Melting point: 207.degree.-208.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3 -DMSO-d.sub.6).delta.: 1.04(t,J=7 Hz,3H),
1.60-1.90(m,2H), 1.97(d,J=2 Hz,3H), 2.43(s,3H), 2.91-3.16(m,2H),
3.93(s,3H), 7.12-7.38(m,3H), 7.72(m,1H), 8.11(m, 1H).
(b) Preparation of
(Z)-3-(4-acetoxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid
##STR125##
7.4 g of (E)-3-(4-acetoxy-3-methoxy-5-propyl-1-naphthyl)-2-methylpropenoic
acid was dissolved in 1.3 liters of acetone, and irradiated with light
from a high pressure mercury lamp through a Pyrex filter at room
temperature for 3 hours. The reaction mixture was concentrated in vacuo
and purified by silica gel column chromatography (3% methanol/chloroform)
to obtain 2.7 g of the titled compound as colorless crystals.
Melting point: 164.degree.-165.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.01(t,J=7 Hz,3H),
1.44-1.92(m,2H), 2.16(d,J=1.8 Hz,3H), 2.38(s,3H), 2.80-3.12(m,2H),
3.79(s,3H), 6.37(br.s,1H), 7.01-7.32(m,4H), 7.44-7.70(m,1H).
Example 17
(E)-3-(4-hydroxy-5-isopropyl-3-methoxy-1-naphthyl)-2methylpropenoic acid
##STR126##
The 5-isopropyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde
obtained in Reference 12 and triethyl 2-phosphonopropionate were reacted
in the same manner as in Example 1 to obtain the titled compound as yellow
crystals.
Melting point: 198.degree.-200.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.37(d,J=6.7 Hz,6H), 1.98(d,J=1.4
Hz,3H), 3.97(s,3H), 4.38-4.77 (m,1H), 6.52(br.s,1H), 7.11(s,1H),
7.20-7.48(m,2H), 7.63(dd,J=2.0 Hz,7.8 Hz,1H), 8.11(s,1H).
Example 18
(Z)-3-(4-hydroxy-5-isopropyl-3-methoxy-1-naphthyl)-2-methylpropenoic acid
##STR127##
The ethyl
(E)-3-(5-isopropyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoa
te obtained in Example 17 were reacted in the same manner as in Example 2
to obtain the titled compound as yellow crystals.
Melting point: 195.degree.-196.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.35(d,J=6.9 Hz,6H), 2.18(d,J=2.0
Hz,3H), 3.81(s,3H), 4.37-4.70 (m,1H), 6.46(br.s,1H), 7.10-7.40(m,4H),
7.56(dd,J=2.0 Hz,7.7 Hz,1H).
Example 19-25
The aldehydes obtained in References 14, 15, 13, 9, 12 and 5 and triethyl
phosphonoacetate were, respectively, reacted in the same manner as in
Example 1 to obtain compounds of Examples 19 to 25 indicated in Table 4.
TABLE 4
__________________________________________________________________________
Intended Compounds
Appear-
Ex- ance Melt-
am-
Structural NMR ing
ple
Formula. Spectrum
Point
No.
Name of Compound
(90 MHz)
(.degree.C.)
chemical formula NMR data (90
__________________________________________________________________________
MHz)
19 (E)-3-(4-hydroxy- 3-methyl-1-naphthyl)- propenoic acid
yellow crystals
194 to 196
##STR128## 2.40(s, 3H), 6.42(d,
J=17.5Hz, 1H), 7.32.about.7.64
(m, 2H), 7.76(s, 1H),
7.96.about.8.44(m, 3H)
(DMSO-d.sub.6)
20 (E)-3-(3-chloro-5- ethyl-4-hydroxy- 1-naphthyl)-propenoic
yellow crystals
over 200 (decom- posed)
##STR129## 1.26(t, J=7Hz, 3H), 3.31(q,
J=Hz, 2H), 6.43(d, J=15Hz,
1H). 7.12.about.7.56(m, 2H),
7.68.about.8.00(m, 2H),
8.16(d, J=15Hz,
1H), 10.14(br.s, 1H),
12.42(br.s,
1H) (DMSO-d.sub.6)
21 (E)-(4-hydroxy-3- methoxy-1-naphthyl)- propenoic acid
pale yellow crystals
178- 180
##STR130## 3.98(s, 3H), 6.43(d,
J=15.4Hz, 1H), 7.20.about.7.50
(m, 2H), 7.64(s, 1H),
7.90.about.8.22(m, 2H),
8.42(d, J=15.4Hz, 1H)
(CD.sub.3 OD)
22
##STR131## 3.90(s, 3H), 4.14(s, 3H),
6.35(d, J=15.4Hz, 1H),
6.85.about.7.97(m, 4H),
8.26(d, J=15.4Hz, 1H)
(400MHz, DMSO-d.sub.6)
23 (E)-3-(4-hydroxy- 3-methoxy-5-methyl- 1-naphthyl)- propenoic
yellow crystals
194- 195
##STR132## 2.86(s, 3H), 3.93(s, 3H),
6.48(d, J=16Hz,
1H), 7.02.about.7.30(m, 2H),
7.68.about.7.92(m, 2H),
8.23(d, J=16Hz, 1H), 9.30(s,
1H), 12.3(br.s,
1H) (DMSO-d.sub.6)
24 (E)-3-(4-hydroxy-5- isopropyl-3-methoxy- 1-naphthyl)- propenoic
yellow crystals
188- 189
##STR133## 1.36(d, J=6.7Hz, 6H), 4.00(s,
3H), 4.40.about.4.80(m, 1H),
6.32(d, J=15.4Hz, 1H),
7.21.about.7.43(m, 3H),
7.49(s, 1H), 7.91(dd,
J=2.0Hz, 7.7Hz, 1H), 8.44(d,
J=15.4Hz, 1H) (CDCl.sub.3)
25 (E)-3-(3-ethoxy- 5-ethyl-4-hydroxy-1- naphthyl)propenoic
yellow crystals
179- 180
##STR134## 1.32(t, J=7Hz, 3H), 1.50(t,
J=7Hz, 3H), 3.32(q, J=7Hz,
2H), 4.22(q, J=7Hz, 2H),
6.34(d, J=15.4Hz, 1H),
7.12.about. 7.40(m, 2H),
7.48(s, 1H), 7.90(dd,
J=2.6Hz, 7.7Hz, 1H), 8.50(d,
J=15.4Hz, 1H) (CDCl.sub.3
-CD.sub.3 OD)
__________________________________________________________________________
Example 26
(E) -3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-butenoic acid
##STR135##
(a) Preparation of ethyl (E) and (z)
-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate
##STR136##
420 mg of 60% sodium hydride was suspended in 10 ml of
N,N-dimethylformamide, to which 3.9 g of triethyl phosphonoacetate was
added at room temperature. After stirring for 15 minutes, a solution of
1.0 g of 5'-ethyl-3'-methoxy-4'-methoxy-methoxy-1'-acetonaphthone in
N,N-dimethylformamide (5 ml) was added. The reaction mixture was stirred
at 90.degree. C. for 3 hours. After cooling to room temperature, ice
cooled water was added, followed by extraction with ethyl acetate. The
organic layer was washed with water, dried with anhydrous magnesium
sulfate-and evaporated. The resultant residue was purified by silica gel
column chromatography (5% ethyl acetate/hexane) to obtain 470 mg of the E
isomer as colorless crystals and 290 mg of the Z isomer as a yellow oil.
(E product)
Melting point: 80.degree.-81.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.30(t,J=7 Hz,6H), 2.59(d,J=1.8
Hz,3H), 3.36(q,J=7 Hz,2H), 3.56(s,3H), 3.93(s,3H), 4.21(q,J=7 Hz,2H),
5.15(s,2H), 5.94(d,J=1.8 Hz,1H), 7.04(s,1H), 7.08-7.28(m,2H), 7.44-7.68
(m,1H).
(Z product)
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.74(t,J=7 Hz,3H), 1.29(t,J=7
Hz,3H), 2.23(d,J=1.8 Hz,3H), 3.34(q,J=7 Hz,2H), 3.57(s,3H), 3.75(q,J=7
Hz,2H), 3.89(s,3H), 5.12(s,2H), 6.11(d,J=1.8 Hz,1H), 6.90(s,1H),
7.00-7.28(m,2H), 7.37-7.54(m,1H).
(b) (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic acid
##STR137##
470 mg of ethyl
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate was
dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran, to which 350 mg
of potassium hydroxide and 2 ml of water were added, followed by refluxing
for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid
and extracted with ethyl acetate. The organic layer was washed with water,
dried over anhydrous magnesium sulfate, and evaporated to obtain 280 mg of
the titled compound as pale yellow crystals.
Melting point: 114.degree.-115.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.:
1.31(t,J=7Hz,3H), 2.62(br.s,3H), 3.37(q,J=7 Hz,2H),
3.59(s,3H), 3.96(s,3H), 5.17(s,2H), 6.00(m,1H),
7.05(s,1H), 7.16-7.36(m,2H), 7.48-7.72(m,1H).
(c) Preparation of
(E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-butenoic acid
##STR138##
280 mg of (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic
acid was dissolved in 8 ml of acetone, to which 1 ml of concentrated
hydrochloric acid was added at room temperature. After stirring for 1
hour, 30 ml of water was added, followed by extraction with ethyl acetate.
The organic layer was washed with water, dried over magnesium sulfate, and
evaporated to obtain 177 mg of the titled compound as pale yellow
crystals.
Melting point: 148.degree.-150.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.34(t,J=7 Hz,3H), 2.61(br.s,3H),
3.34(q,J=7 Hz,2H), 3.98(s,3H), 6.00(br.s,1H), 6.40(br.s,1H), 6.98-7.34
(m,3H), 7.42-7.70(m,1H).
Example 27
(Z)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-butenoic acid
##STR139##
(a) Preparation of
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic acid
##STR140##
In the same manner as in Example 1(b), 180 mg of the titled compound was
obtained, as pale yellow crystals, from 290 mg of the ethyl
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate.
Melting point: 116.degree.-117.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.28(t,J=7 Hz,3H), 2.20(d,J=1.5
Hz,3H), 3.10-3.56(m,2H), 3.44(s,3H), 3.84(s,3H), 5.12(s,2H), 6.02(d,J=1.5
Hz,1H), 6.84(s,1H), 7.00-7.44(m,3H).
(b) preparation of
(Z)-31(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-butenoic acid
##STR141##
In the same manner as in Example 1(c), 125 mg of the titled compound was
obtained, as pale yellow crystals, from 180 mg of
(Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic acid.
Melting point: 185.degree.-188.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3 -DMSO-d.sub.6).delta.: 1.33(t,J=7Hz, 3H)
2.21(d,J=1.8 Hz,3H), 3.31(q,J=7 Hz,2H), 3.93(s,3H), 6.13 (m,1H),
6.44(br.s,1H), 6.93(s,1H), 7.04-7.57 (m,3H).
Example 28
(E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-heptenoic acid
##STR142##
The 5'-ethyl-3'-methoxy-4'-methoxymethoxy-1'-valeronaphthone obtained in
Reference 7 was reacted in the same manner as in Example 26 to obtain the
titled compound as pale yellow crystals.
Melting point: 139.degree.-140.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 0.68-0.96(m,3H), 1.12-1.56(m,6H),
2.88-3.20(m,2H), 3.32(q,J=7 Hz,2H), 3.96(s,3H), 5.88(s,1H), 6.36(br.s,1H),
6.96(s,1H), 7.04-7.30(m,2H), 7.40-7.64(m,1H).
Example 29
(E)-3-3-isopropyl-4-hydroxy-5-methyl-1-naphthyl)propenoic acid
##STR143##
(a) preparation of ethyl
(E)-3-(4-acetoxy-3-isopropyl-5-methyl-1-naphthyl)propenoate
##STR144##
0.5 g of 4-acetoxy-3-isopropyl-5-methyl-1-naphthalenecarbaldehyde and 11 g
of (carbethoxymethylene)triphenylphosphorane were dissolved in 50 ml of
tetrahydrofuran and refluxed for 1 hour. The reaction mixture was cooled
to room temperature and concentrated in vacuo. The resultant residue was
purified by silica gel column chromatography (10% ethyl acetate/hexane) to
obtain 0.5 g of the titled compound as pale yellow crystals.
Melting point: 122.degree.-123.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.29(d,J=7 Hz,6H), 1.37(t,J=7
Hz,3H), 2.49(s,6H), 3.14(m,1H), 4.27(q,J=7 Hz,2H), 6.45(d,J=16 Hz,1H),
7.58(s,1H), 6.94-8.04(m,3H), 8.19(d,J=16 Hz,1H).
(b) (E)-3-(3-isopropyl-4-hydroxy-5-methyl-1-naphthyl)propenoic acid
##STR145##
0.5 g of ethyl (E)-3-(4-acetoxy-3-isopropyl-5-methyl-1-naphthyl)propenoate
was dissolved in 50 ml of ethanol, to which a potassium hydroxide aqueous
solution (potassium hydroxide 1.6 g/water 10 ml) was added, followed by
refluxing for 30 minutes. The solution was cooled to 0.degree. C. and
water was added. Dilute hydrochloric acid was added to make the aqueous
phase acidic and extracted with ethyl acetate. The organic phase was
washed with brine, dried with anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (40%.ethyl acetate/hexane) and the resultant crystals were
recrystallized from a mixed solvent of isopropyl ether and ethyl acetate
(1:1) and washed with isopropyl ether and hexane (3:7) to obtain 0.19 g of
the titled compound as yellow needle.
Melting point: 171.degree.-174.degree. C.
.sup.1 H-NMR(90 MHz, DMSO-d.sub.6).delta.:
1.27(d,J=7 Hz,6H), 2.50(s,3H), 3.55(m,1H),
6.49(d,J=16 Hz,1H), 7.23-7,51(m,1H), 7.77(s,1H), 7.87-8.15 (m,2H),
8.31(d,J=16 Hz,1H), 9.50(br.s,1H).
Example 30
Ethyl (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)propenoate
##STR146##
To a solution of 1.3 g of ethyl
(E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)propenoate in ethanol
(10 ml) was added 1 ml of concentrated hydrochloric acid and stirred at
room temperature for 2 hours. Water was added to the reaction mixture and
extracted with ethyl acetate. The organic layer was washed with water and
brine and dried over anhydrous magnesium sulfate. After evaporation,
hexane was added for crystallization to obtain 0.76 g of the titled
compound as pale yellow crystals.
Melting point: 75.degree.-76.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.31(t,J=7 Hz,3H), 1.37(t,J=7
Hz,3H), 3.33(q,J=7 Hz,2H), 4.00(s,3H), 4.27(q,J=7 Hz,2H), 6.35(d,J=15
Hz,1H), 6.60(s,1H), 7.09-7.36(m,2H), 7.47(s,1H), 7.91(dd,J=2 Hz,8 Hz,1H),
8.44(d,J=15 Hz,1H).
Example 31
Ethyl (E)-3-(4-hydroxy-3-methyl-1-naphthyl)-propenoate
##STR147##
In the same manner as in Example 30, the titled compound was obtained, as
reddish orange crystals, from ethyl
(E)-3-(4-methoxymethoxy-3-methyl-1-naphthyl)-propenoate.
Melting point: 122.degree.-124.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.: 1.36(t,J=7 Hz,3H), 2.43(s,3H),
4.27(q,J=7 Hz,2H), 6.41(d,J=15 Hz,1H), 7.19-7.67(m,2H), 7.60(s,1H),
7.87-8.39 (m,2H), 8.44(d,J=15 Hz,1H).
Example 32
(E)-1-[3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-1-oxo-2-propenyl]piperidi
ne
##STR148##
(a)
(E)-1-[3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-1-oxo-2-propenyl]
piperidine
##STR149##
0.15 g of 60% sodium hydride was suspended in 20 ml of
N,N-dimethylformamide, to which 1.15 g of
N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room
temperature. After stirring for 10 minutes, a solution of 800 mg of
5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in
N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20
minutes, water was added, followed by extraction with ethyl acetate. The
combined extracts were washed with water and dried over anhydrous
magnesium sulfate. After removal of the solvent, the resultant residue was
purified by silica gel column chromatography (30% ethyl acetate/hexane) to
obtain 1.1 g of the titled compound as pale yellow crystals.
Melting point: 85.degree.-86.degree. C.
.sup.1 H-NMR(90 MHz, CDCl.sub.3).delta.:
1.28(t,J=7 Hz,3H), 1.44-1.80(m,6H), 3.34(q,J=7 Hz,2H),
3.56(s,3H), 3.44-3.80(m,4H), 3.98(s,3H), 5.16(s,2H),
6.76(d,J=15.4 Hz,1H),7.16-7.32(m,2H), 7.38(s,1H), 7.80-8.00(m,1H),
8.32(d,J=15.4 Hz,1H).
(b)
(E)-1-[3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-1-oxo-2-propenyl]piperid
ine
##STR150##
960 mg of
(E)-1-[3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-1-oxo-2-propenyl]
piperidine was dissolved in 50 ml of acetone, to which 1 ml of concentrated
hydrochloric acid was gradually added at room temperature. After stirring
at room temperature for 5 hours, the reaction mixture was slowly poured
into water. The resultant crystals were collected by filtration, washed
with water and dried to obtain 760 mg of the titled compound as yellow
crystals.
Melting point: 176.degree.-179.degree. C.
.sup.1 H-NMR (90 MHz, CDCl.sub.3).delta.:
1.30(t,J=7Hz,3H), 1.42-1.80(m,6H), 3.32(q,J=7 Hz,2H),
3.44-3.78(m,4H), 4.00(s,3H), 6.52(s,1H),
6.72(d=15.4 Hz,1H), 7.08-7.28(m,2H), 7.36(s,1H),
7.88(dd,J=2.6 Hz,7.7 Hz,1H), 8.32(d,J=15.4 Hz,1H).
Example 33 and 34
5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalene-carbaldehyde was reacted
with a suitable Wittig agent. The product was treated in the same way as
shown in Example 1.
Example 36 to 41
The aldehyde obtained in Reference Examples 23, 24, 22, 12, 16 and 5 and
ethyl diethylphosphonoacetate were treated in the same way as shown in
Example 1.
Table 5 shows the results of Examples 33, 34 and 36 to 41.
Example 35
(E)-2-cyclopentyl-3-(4-hydroxy-3-methoxy-5-methyl-1naphthyl)propenic acid
##STR151##
When 3-methoxy-4-methoxymethoxy-5-methyl-1-naphthalene carbaldehyde
obtained in Reference Example 9 and triethyl 2-phosphono cyclopentyl
acetate were processed in the same procedures as those in Example 1, the
above-captioned compound was obtained as yellow crystals.
m.p.; 173.degree..about.175.degree. C.
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6).delta.: 1.3.about.2.1 (m, 8H),
2.7.about.3.1 (m, 1H), 2.85 (s, 3H), 3.86 (s, 3H), 6.98.about.7.58 (m,
4H), 7.83 (s, 1H), 8.99 (s, 1H), 12.41 (br. s, 1H)
TABLE 5
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No.
chemical formula appearance
NMR data (90 MHz) m.p.(.degree.C.)
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33
##STR152## light yellow crystals
1.32(t, J=7Hz, 3H), 2.74(t, J=7Hz, 2H),
3.32(s, 3H), 3.33(q, J=7Hz, 2H), 3.62(t,
J=7Hz, 2H), 3.98(s, 3H), 6.45(s, 1H),
7.10.about.7.54(m, 1H),
7.54.about.7.70(m, 1H), 7.72(s, 1H),
8.38(s, 1H), (CDCl.sub.3)
157.about.158
34
##STR153## light yellow crystals
1.24(t, J=7Hz, 3H), 3.10.about.3.44(m,
2H), 3.66(s, 3H), 3.85(s, 2H),
6.68.about.7.65(m, 7H), 8.14(s, 1H),
9.17(s, 1H), 12.67(br.s,
1H) (DMSO-d.sub.6) 160.about.163
36
##STR154## yellow crystals
1.72.about.2.02(m, 2H),
3.15.about.3.44(m, 4H), 3.21(s, 3H),
3.94(s, 3H), 6.50(d, J=16Hz, 1H),
7.04.about.7.36(m, 2H),
7.69.about.7.96(m, 2H), 8.27(d, J=16Hz,
1H), 9.43(s, 1H), 12.28(br.s, 1H)
(DMSO-d.sub.6) 186-188 decompositi
on
38
##STR155## light yellow crystals
1.36(t, J=7Hz, 3H), 3.11(q, J=7Hz, 2H),
3.99(s, 3H), 6.16(d, J=16Hz, 1H),
7.14.about.7.46(m, 3H), 8.05(dd, J=3Hz,
7Hz, 1H), 8.64(d, J=16Hz,
1H) (CDCl.sub.3) 168.about.169
37
##STR156## yellow crystals
1.30(t, J=7Hz, 3H), 2.77(q, J=7Hz, 2H),
3.98(s, 3H), 6.37(d, J=16Hz, 1H),
7.18.about.7.38(m, 1H), 7.50(s, 1H),
7.82(br.s, 1H), 8.06(d, J=7Hz, 1H),
8.44(d, J=16Hz, 1H) (CDCl.sub.3 -DMSO-d.su
b.6) 161.about.162
39
##STR157## yellow crystals
1.32(t, J=7Hz, 3H), 3.34(q, J=7Hz, 2H),
3.48(s, 3H), 3.56.about.3.8(m, 2H),
4.10.about.4.36(m, 2H), 6.36(d, J=15Hz,
1H), 7.14.about.7.50(m, 2H), 7.56(s, 1H),
.94(d, J=7Hz, 1H), 8.52(d, J=15Hz, 1H)
(CDCl.sub.3) 142.about.143
40
##STR158## yellow crystals
0.80.about.1.10(m, 3H),
1.16.about.1.62(m, 7H), 1.62.about.2.04(m,
2H), 3.32(q, J=7Hz, 2H), 4.16(t, J=7Hz,
2H), 6.36(d, J=15Hz, 2H), 6.62(br.s, 1H),
7.12.about. 7.42(m, 2H), 7.50(s, 1H),
7.92(dd, J=2.6Hz, 7Hz, 1H), 8.56(d,
J=15Hz, 1H) (CDCl.sub.3)
137.about.138
41
##STR159## yellow crystals
1.30(t, J=7Hz, 3H), 3.30(q, J=7Hz, 2H),
5.20(s, 2H), 6.30(d, J=15Hz, 1H),
7.10.about.7.70(m, 8H), 7.90(dd, J=2.6Hz,
7Hz, 1H), 8.50(d, J=15Hz,
1H) (CDCl.sub.3) 172.about.174
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